Endogenous opioid systems alterations in pain and opioid use disorder

Introduction

The intersection between pain and opioid use presents a major dilemma for public health. Efforts to curb the burden of the ongoing opioid crisis continue to be challenged by the need to provide adequate relief for pain patients and at the same time lessen the negative impact of opioid misuse. Pain is extremely prevalent with over half of US adults reporting pain symptoms within the past 3 months (Lucas et al., 2021). Similarly, detriments of opioid abuse are evident in the annual increases in opioid overdose deaths, with the most recent provisional estimates exceeding 80,000 in 2021 (Ahmad et al., 2022). Although the prevalence of problematic opioid use in pain patients is difficult to pin-point for a myriad of reasons (Ballantyne, 2015; Voon et al., 2017), estimates derived from a number of metanalyses suggest rates of problematic prescription opioid use may occur in >80% of pain patients (Minozzi et al., 2013; Ballantyne, 2015; Chou et al., 2015; Vowles et al., 2015; Voon et al., 2017). Collectively, pain and opioid use pose tremendous societal costs, with pain-related health care and lost productivity exceeding $635 billion and opioid abuse-related health care, criminal justice, lost productivity, reduced quality of life, and life lost due to overdose exceeding $1.03 trillion annually (Institute of Medicine Committee on Advancing Pain Research, 2011; Gaskin and Richard, 2012; Florence et al., 2021). Linking the putative relationship between pain and maladaptive opioid use, is the endogenous opioid system, a primary biological substrate of pain and opioid reward. In the present review, we examine how pain and concurrent opioid use may disrupt endogenous opioid system function leading to alterations in reward signaling pathways and ultimately, higher risk for negative outcomes associated with opioid use.

Problematic opioid use in the context of pain

In 2019, the National Survey on Drug Abuse reported that almost all (>96%) instances of opioid misuse, or use deviating from physicians’ instructions, was restricted to prescription opioid pain medications (Center for Behavioral Health Statistics and Quality, 2019). This same report indicated that among those that misused prescription opioids, the most common reason for misuse was to relieve physical pain (65%). Based on this evidence and the lack of therapeutic alternatives to prescription opioids suggests that the US is undertreating pain or undermining an overlapping and vulnerable population. The former could have likely been fueled by pain management initiatives in the 1990s that recognized pain as a fifth vital sign (Morone and Weiner, 2013; Meisenberg et al., 2018). This notion encouraged physicians to prioritize pain reduction through the liberalization of opioid prescriptions (Compton and Volkow, 2006; U.S. Department of Health and Human Services, 2019) which led to the initial wave of prescription overdose deaths (Rudd et al., 2016). This was addressed by several opioid diversion and mitigation strategies, including revisions to opioid prescribing practices in 2016 by the Center of Disease Control (CDC) that limit the number of opioid prescriptions (Lappin, 2016; Volkow and McLellan, 2016). Although these efforts appeared to bring prescription overdoses to a plateau, synthetic opioid overdoses (both illicit and prescribed) increased at alarming rates (CDC WONDER, 2018). It is difficult to pin down whether the continued rise in opioid overdoses was driven by the unmet needs of pain patients, growth in illicit markets, or a combination of both. Despite additional government-backed initiatives intended to curb opioid use and facilitate research for pain management alternatives (U.S. Department of Health and Human Services, 2019), the prevalence of chronic pain and opioid overdose deaths continue to rise each year (Goldstick et al., 2021; Zajacova et al., 2021; Ahmad et al., 2022), and have even been amplified by the COVID-19 pandemic (Fallon et al., 2021; Manchikanti et al., 2021; Soares et al., 2021). The National Institute of Health’s (NIH) most recent endeavor, the HEAL initiative (Helping to End Addiction Long-term), recognized the need to address the opioid crisis through improvements to pain management (Wandner et al., 2022). As such, our ability to curtail opioid abuse and improve the treatment of pain relies heavily on our capacity to understand the neurobiological mechanisms underlying pain and opioid systems.

According to the International Association for the Study of Pain (IASP), pain is defined as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” (Raja et al., 2020). The intersection between these two dimensions of pain—sensation and emotion—present a substantial problem for chronic pain patients on long-term opioid therapy which can play a synergistic role in perpetuating pain, mood disruptions, and problematic opioid use. The occurrence of mood disorders can predict not only opioid misuse liability (NIDA, 2008; Davis et al., 2017; Center for Behavioral Health Statistics and Quality, 2019; Jones and McCance-Katz, 2019; Smit et al., 2020) but also, susceptibility to pain conditions (Viana et al., 2018; Rizvi et al., 2021). Likewise, patients with opioid use disorder (OUD), a chronic and relapsing disorder characterized by persistent and compulsive drug-seeking behavior despite negative outcomes, frequently report comorbidities of chronic pain (up to 65%) and mood disorders (up to 82%) (Davis et al., 2017; Hser et al., 2017; Peciña et al., 2018; Jones and McCance-Katz, 2019; Higgins et al., 2020; Latif et al., 2021). It is therefore not surprising that chronic pain patients are 2–3 times more likely to meet diagnostic criteria for an anxiety, mood, and mental disorders (Pereira et al., 2017) and are at higher risk (>50%) for developing opioid or substance use disorder (Højsted and Sjøgren, 2007; Morasco et al., 2011). Collectively, the co-occurrence of pain, mood disruptions, and problematic opioid use can have additive effects on the severity and risk for the other. The extensive overlap of these conditions alludes to a common underlying mechanism; and while each of these conditions are associated with dysfunction across multiple biological systems, one potential source of shared functional disruption lies within the endogenous opioid system (Jarcho et al., 2012; Witkin et al., 2014; Peciña et al., 2018; Jones and McCance-Katz, 2019; Toubia and Khalife, 2019).

The endogenous opioid system

Both pain and exogenous opioids can disrupt function of the endogenous opioid system (Roeckel et al., 2016) and similarly, alterations in endogenous opioid activity can predict variations in pain thresholds, opioid-induced analgesia, and the proclivity for opioid misuse and abuse (Corder et al., 2018; Jassar et al., 2019; Llorca-Torralba et al., 2019a; Massaly and Morón, 2019; Bodnar, 2021). The endogenous opioid system plays an important role in analgesia, but it is also critically involved in autonomic regulation, immunological responses, gastrointestinal function, learning and memory, and many other functions (Bodnar, 2021). As such, the endogenous opioid system is crucial for maintaining homeostasis and alterations in its activity are largely state dependent (Darcq and Kieffer, 2018; Valentino and Volkow, 2018). This system is also highly integrated with other biological systems involved in stress regulation, mood, and reward such as the endocannabinoid, serotonin, oxytocin, vasopressin, and dopamine (DA) systems and the hypothalamic adrenal pituitary axis (Leknes and Tracey, 2008; Toubia and Khalife, 2019; Emery and Akil, 2020; Koob, 2020; Bodnar, 2021; Mohammadkhani and Borgland, 2022). Implicitly, the extensive crosstalk between these contributes to the highly adaptive nature of the opioid system and its ability to acutely respond to noxious stimuli. However, chronic perturbations to opioid systems can leave the system vulnerable to dysfunction and have debilitating consequences (Stoeber et al., 2018). Here, we focus on the impact of pain and opioids on function of the endogenous opioid system and reward pathways and examine their putative role in provoking maladaptive patterns of opioid use and OUD.

Opioids

Opioids are natural, synthetic, or semi-synthetic chemicals acting on opioid receptors to produce analgesia among other peripheral effects (Zöllner and Stein, 2007). Opium is a dried milky exudate obtained from the unripe seed pods of the opium poppy, papaver somniferum (Brownstein, 1993). Among the dozens of alkaloids found in opium, the pharmacologically relevant constituents include morphine (10–15%), codeine (1–3%, noscapine (4–8%), papaverine (1–3%), and thebaine (1–2%) (Zöllner and Stein, 2007). The antiquity of opium for medicinal use was documented as early as ∼2100 BCE in Sumerian medical tablets (Duarte, 2005). The unrivaled ability of opium to relieve pain was recognized in texts for millennia, but the therapeutic application of opioids was transformed when a young German apothecary’s assistant, F.W.A. Sterürner, isolated crystalline morphine (1803–1817), naming it after Greek god of sleep and dreams (Krishnamurti and Rao, 2016). The subsequent invention of the hypodermic syringe needle in the 1850s facilitated the use of morphine for surgical procedures, pain relief, and as an adjunct to general anesthetics (Brownstein, 1993). Since then, the broad application of various opioid analgesics has facilitated a greater understanding of the opioid system and the clinical utility of opioids for pain management.

The existence of opioid receptors was first proposed in the 1950s (Beckett and Casy, 1954), but it was not until the 1970s that different bioassays began to identify stereospecific binding sites for opioids in the brain (Pert and Snyder, 1973; Simon et al., 1973; Terenius, 1973; Martin et al., 1976; Lord et al., 1977). These studies revealed that exogenous opioid ligands produce their narcotic effects through actions at different opioid receptors which led to the discovery that endogenous opioid-like peptides can produce similar effects through their activity at the same peptide receptors (Cox et al., 1976; Hans et al., 1977; Olson et al., 1979). The first evidence of distinct opioid receptor types was determined by detailing the actions of several analgesic drugs. As such, the first two opioid receptor types were named after the prototypic drugs used in these studies to distinguish them, mu (μ) for morphine and kappa (κ) for ketocyclazocine (Martin et al., 1976). Pharmacological analysis revealed a third opioid receptor type in the mouse vas deferens that exhibited a pharmacological profile markedly different from those previously identified (μ and κ) and was accordingly, named delta (δ) to signify this difference (Lord et al., 1977). The heterogeneity of these receptor types was later confirmed when distinct mRNAs for each receptor type were cloned and characterized (Evans et al., 1992; Kieffer et al., 1992; Chen et al., 1993; Yasuda et al., 1993). Together, the μ, κ, and δ opioid receptors (MOPR, KOPR, DOPR, respectively) are considered the classical opioid peptide receptors based on their structural homology and sensitivity to the non-selective opioid receptor antagonist, naloxone (Dietis et al., 2011). A fourth opioid receptor-like (OPRL1) gene was later revealed to encode a receptor with a primary structure analogous to previously identified opioid receptors and yet, it lacked sensitivity to traditional opioid ligands (Bunzow et al., 1994; Mollereau et al., 1994). As such, OPRL1 remained an ‘orphan’ receptor until two independent groups isolated its endogenous ligand, nociception (Meunier et al., 1995) or orphanin FQ (Reinscheid et al., 1995) (N/OFQ), for which the OPRL1 or N/OFQ opioid receptor is referred to here on as NOPR. While MOPR, KOPR, DOPR, and NOPR comprise the four major opioid receptor systems due to homology in structure and function, NOPR is often excluded from “classical” opioid receptor types based on its lack of sensitivity to naloxone or prototypical opioid ligands.

Four major opioid peptide families are commonly associated with complimentary opioid receptor systems for which they exhibit preferential activity: β-endorphins (MOPR), dynorphins (KOPR), enkephalins (DOPR), and N/OFQ (NOPR) (Hughes et al., 1977; Nakanishi et al., 1979; Horikawa et al., 1983; Pathan and Williams, 2012; Shenoy and Lui, 2018). However, despite greater selectivity of these endogenous ligands and their respective receptors, the activity of both endogenous and exogenous opioids at distinct receptor types is rarely exclusive to one family and can often activate multiple receptor types to varying degrees (Stein, 2016). Opioid receptors are seven-transmembrane G protein-coupled receptors (GPCR) that generally couple to inhibitory G proteins, thereby reducing signal transduction and neurotransmission by engaging several second- and third-messenger systems and regulating ion channel activity (Zöllner and Stein, 2007; Al-Hasani and Bruchas, 2011; Toll et al., 2016; Corder et al., 2018). Different opioids can also engage biased signaling pathways to preferentially activate GPCR-dependent signaling or β-arrestin-dependent signaling, which can produce analgesia or unwanted side-effects, respectively (Ballantyne and Chavkin, 2020). Allosteric binding sites on opioid receptors, distinct from orthostatic sites or the ligand binding pocket, can also modulate opioid receptor function through activation by various other neurotransmitters and neuropeptides (Kathmann et al., 2006; Burford et al., 2015; Remesic et al., 2017; Livingston and Traynor, 2018). For example, cannabidiol (CBD), an exogenous cannabinoid ligand, can act as a negative allosteric modulator at MOPR or DOPR in rat cerebral cortices to reduce their function (Kathmann et al., 2006). Positive allosteric modulators for MOPR have also been sought after as they may reduce some of the unwanted side-effects attributed to traditional opioid medications or facilitate the activity of endogenous opioids (Burford et al., 2015). Adding another layer of complexity to opioid receptor signaling is the fact that different opioid receptors can associate with each other to form heteromers (e.g., MOPR-DOPR, DOPR-KOPR, KOPR-MOPR). For example, DOPR antagonism of DOPR-MOPR heteromers can act to enhance MOPR agonist-mediated analgesia (Gomes et al., 2004). The complexity of opioid receptor signaling mechanisms shed light on the multiple means by which opioid system function can be disrupted.

Opioid receptors are among the most widely expressed receptors in the central and peripheral nervous systems, although the composition and distribution of different opioid receptor types varies across regions (Corder et al., 2018). In the periphery, opioid receptors expressed in the lungs, heart, kidney, small intestine, and pancreas, can modulate organ function, inflammation, as well as multiple homeostatic processes (Peng et al., 2012). Opioid receptors can also be found in neuroendocrine (adrenals, pituitary), immune (leukocytes), and ectodermal cells, where they can modulate nociception and inflammation (Zöllner and Stein, 2007; Stein, 2013). In the context of pain, opioid receptors are ideally situated among, and connected with, somatosensory neurons of dorsal root ganglion (DRG) and second-order neurons of the dorsal horn of the spinal cord where they transmit ascending nociceptive signals to cortical areas through the spinothalamic, spinoreticular, and spinoparabrachial pathways (Basbaum and Fields, 1984; Marchand, 2008; DosSantos et al., 2017; Ringkamp et al., 2018). Local release of endogenous opioids or acute application of exogenous opioids at injury sites can suppress DRG activity to reduce nociceptive signaling and pain perception (Dickenson et al., 1990; Stein et al., 2003; Spahn et al., 2017; Corder et al., 2018; Massaly et al., 2020). Similarly, top-down regulation by opioid receptor systems within the periaqueductal gray (PAG) and rostral ventral medulla (RVM) can exert descending modulatory control over nociceptive signal transduction (Marchand, 2008; Ringkamp et al., 2018). The level of top-down control over anti-nociceptive responses can also be influenced by opioid receptor systems in other brain regions involved in cognition, affect, sensation, and motivation (Corder et al., 2018; Bannister and Dickenson, 2020; Dickenson et al., 2020). As such, the central and peripheral presence of opioid systems yields the ability of opioid receptors to functionally modulate reward-aversion networks through ascending and descending modes of control, and therefore, play a substantial role in aversive pain states, reward from pain relief, and hedonic balance (Darcq and Kieffer, 2018).

Proper functioning of the endogenous opioid system is essential for survival mechanisms involved in reward- and aversion-based learning and behavior. When the integrity of this system becomes compromised, the ability to integrate opioid reward- and pain aversion-related information will also become impaired. Among the many debilitating consequences associated with compromised opioid system function, is the risk of OUD. After repeated drug exposure, reward-processing centers can undergo neuroadaptations that leave affected individuals with enhanced incentive salience and habit formation, impulsivity, stress reactivity, and negative affect in the absence of drug; thereby producing overall disruptions in motivation (Koob and Volkow, 2010). As a result, maladaptive drug use is perpetuated through cycles of binge/intoxication, withdrawal/negative affect, and preoccupation/craving (Koob and Volkow, 2010). OUD and other substance use disorders are linked with adaptations to the opioid system (Darcq and Kieffer, 2018) because of its central role in reward processing (le Merrer et al., 2009). Therefore, the ability of the opioid system to regulate both pain states and the actions of opioid drugs may exacerbate the risk for the development of OUD in pain patients on long-term opioid therapies. Here, we focus on adaptations within mesolimbic reward pathways and the putative synergistic effects of pain and opioid use in driving opioid misuse liability.

μ Opioid receptor

The role of MOPR in mediating opioid-dependent analgesia and reward provides support for the abundance of research on this opioid receptor family. The analgesic effects of MOPR activity are attributed to their hyperpolarizing effects and suppression of neuronal activity. This is regulated by G_αi-mediated inhibition of cAMP production (Raffa et al., 1994), activation of G protein-coupled inwardly rectifying potassium (GIRK) channels (Ikeda et al., 2000), G_βγ -mediated inhibition of L-type calcium channels (Bourinet et al., 1996), and inhibition of voltage-dependent calcium channels (VDCC) (Saegusa et al., 2000). Alternatively, β-arrestins can modulate MOPR signaling by decoupling the receptor from G proteins and facilitating receptor internalization (Siuda et al., 2017; Cong et al., 2021). β-arrestins can also engage multiple intracellular signaling cascades independent of G proteins (Macey et al., 2006) and biased signaling mechanisms through β-arrestins or G proteins often produce distinct effects (discussed below).

Endogenous MOPR agonists, like β-endorphins, can be locally released at injury sites to provide acute pain relief through their signaling at the MOPR (Hassan et al., 1993; Truong et al., 2003; Stein et al., 2009). Similarly, acute administration of exogenous MOPR agonists, like morphine, can provide both pain relief and reinforcement. Evidence from positron emission tomography (PET) studies in humans demonstrate that acutely painful stimuli increase MOPR activity in multiple brain regions, including those implicated in nociception and reward processing, such as the PAG and the nucleus accumbens (NAc), respectively (Zubieta et al., 2001, 2002; Bencherif et al., 2002). Relative to pain-free conditions, acute pain enhances MOPR activity while its activity is decreased under conditions of chronic pain. In animal models of neuropathic pain, MOPR expression is downregulated in the spinal cord, DRG, and several cortical regions in the days and weeks following injury (Porreca et al., 1998; Zhang et al., 1998; Rashid et al., 2004; Pol et al., 2006; Thompson et al., 2018). Similarly, patients with chronic lower back pain exhibit lower circulating levels of β-endorphin (Bruehl et al., 2012, 2014, 2017, 2013; Rhodin et al., 2013), while deficits in MOPR binding potential have been linked with multiple pain conditions including fibromyalgia, chronic migraine, trigeminal neuropathic pain, and chronic lower back pain (Harris et al., 2007; DosSantos et al., 2012; Hagelberg et al., 2012; Martikainen et al., 2013; Schrepf et al., 2016; Jassar et al., 2019; Toubia and Khalife, 2019). Therefore, the function of the MOPR system can differ depending on the persistence of pain conditions, losing efficacy over time.

Importantly, MOPR activity can contribute to both sensational and emotional aspects of pain. In healthy controls, baseline MOPR binding can predict pain thresholds, such that lower MOPR binding in multiple cortical regions is associated with higher pain sensitivity (Zubieta et al., 2001, 2002; Hagelberg et al., 2012). Moreover, MOPR binding is negatively correlated with affective pain ratings (Zubieta et al., 2001, 2002), adding further support to the idea that MOPR activity can modulate sensory and affective components of pain. In patients with various chronic pain conditions, the ability of MOPR binding to predict pain sensitivity is similar. For example, patients with trigeminal neuropathic pain exhibit reduced MOPR binding in the NAc which is negatively correlated with pain ratings (DosSantos et al., 2012). Consistent with this relationship, reduced MOPR binding in the prefrontal cortex is associated with migraine severity (DaSilva et al., 2014). Similar results have been recapitulated in rodent models of neuropathic pain. Months after spared nerve injury, rats show reduced MOPR availability and expression in the insula, caudate putamen, and motor cortices, and these levels are correlated with deficits in sucrose preference, a measure of anhedonia (Thompson et al., 2018). Together, these findings indicate that chronic pain disrupts MOPR function to negatively regulate sensory and affective components of pain.

The MOPR system is also influenced by acute or chronic exposure to exogenous opioids. In patients undergoing surgery under general anesthesia, plasma β-endorphin levels are increased, and this effect is inhibited by administration of fentanyl, a potent MOPR agonist (Dubois et al., 1982; Cork et al., 1985). Fentanyl administration also induces MOPR phosphorylation in the striatum of mice at sites involved in receptor desensitization and internalization (Macey et al., 2006), suggesting that acute opioid exposure can have rapid effects on receptor desensitization and tolerance. In contrast, MOPR antagonism increases β-endorphin levels (Hargreaves et al., 1986), adding further support to the idea that endogenous β-endorphin release is regulated by MOPR activity. Chronic opioid exposure can have detrimental effects on endogenous opioid production and MOPR system function. For example, chronic morphine treatment reduces expression levels of the β-endorphin precursor protein, proopiomelanocortin (POMC), in rats (Bronstein et al., 1990; Wardlaw et al., 1996; Przewlocki, 2004), and reduces MOPR density in β-endorphin-expressing neurons of the hypothalamus (site of synthesis) in guinea pigs (Zhang et al., 1996). As such, chronic exposure to exogenous MOPR agonists reduce MOPR system function by reducing endogenous production of MOPR agonists (β-endorphins) and overall MOPR availability. Chronic opioid exposure can also alter function of remaining MOPR by producing a switch in MOPR G-protein coupling from Gi/o to Gs, leading to activation of adenylyl cyclase rather than inhibition (Wang et al., 2005). MOPR activation and subsequent phosphorylation by GPCR kinases can also lead to the recruitment of β-arrestins, which—in conjunction with many other effectors—leads to MOPR receptor desensitization and internalization (Koch and Höllt, 2008; Roeckel et al., 2016; Corder et al., 2017; Derouiche et al., 2020; Massaly et al., 2021). MOPR phosphorylation at sites involved in receptor desensitization and internalization are observed in mice seven days after partial sciatic nerve ligation, a manipulation that produces tolerance to both the analgesic and conditioned reinforcing properties of morphine (Petraschka et al., 2007). Together, these disruptions to endogenous opioid production and MOPR function in response to chronic opioid exposure can lead to long-term plasticity underlying the development of opioid-induced hyperalgesia, analgesic tolerance, and negative affect, contributing to problematic opioid use.

The ability of pain and exogenous opioids to modify MOPR system function can lead to alterations within the mesolimbic reward pathway that may “prime” the system to be more vulnerable to the abuse of opioids, alcohol, and other substances of abuse (Contet et al., 2004). Opioid activity at MOPR produces rewarding effects by hyperpolarizing GABAergic inputs onto ventral tegmental area (VTA) DA neurons, thereby disinhibiting DA release (Elman and Borsook, 2016; Mitsi and Zachariou, 2016; Stoeber et al., 2018). Local infusion of MOPR agonists in the VTA is sufficient to produce reinforcing behaviors and conditioned reward-seeking behavior (Devine and Wise, 1994). Additionally, VTA MOPR function is necessary for opioid-dependent reward (Cui et al., 2014). Based on the ability of opioids to provide both positive reinforcement and pain relief, it seems evident that pain-induced alterations on MOPR signaling within mesolimbic circuits may facilitate tendencies toward opioid abuse (Koob, 2020). A large body of evidence indicates that pain augments opioid reward thresholds by disrupting DA transmission within the mesolimbic system (Hipólito et al., 2015; Martikainen et al., 2015; Taylor et al., 2016; Selley et al., 2020; Ren et al., 2021). This is regulated at least partly by deficits in MOPR system function (Markovic et al., 2021). Preclinical studies have shown that inflammatory and nerve injury pain reduces MOPR agonist efficiency at silencing VTA GABAergic transmission (Hipólito et al., 2015; Taylor et al., 2015), thus decreasing the ability of MOPR agonists to disinhibit VTA DA neurons (Ozaki et al., 2004, 2003, 2002; Hipólito et al., 2015) and evoke DA release in the nucleus accumbens (NAc) (Niikura et al., 2010; Hipólito et al., 2015; Taylor et al., 2015). These pain-induced deficits in mesolimbic function significantly dampen the rewarding properties of MOPR agonists. For example, rats with sciatic nerve ligation exhibit reduced placed preference induced by intra-VTA administration of the MOPR agonist, DAMGO, or systemic administration of morphine—an effect paralleled by attenuated MOPR binding in the VTA (Niikura et al., 2008). Consistent with this idea, chronic pain patients at low risk for opioid misuse exhibit less pain-induced activation of MOPR in the NAc, and this effect is associated with fewer mood disturbances and negative affect (Ballester et al., 2022). Taken together, MOPR signaling is a primary mechanism by which opioids yield high potential for abuse. As such, the MOPR system has received interest as therapeutic target for the treatment of chronic pain and OUD since the 1960s. Methadone, a long-acting MOPR agonist, has been used as a substitution therapy for chronic pain patients with long-term opioid therapy and maintenance treatment for patients with OUD (Kreek, 1973, 1991, 2000; Ferrari et al., 2004; Axelrod and Reville, 2007; Shi et al., 2008; Mattick et al., 2009; Kreek et al., 2010). The unique pharmacokinetic profile of methadone (slow onset, slow offset) yields a useful strategy to target the MOPR system while reducing the potential for opioid abuse, but the efficacy of these treatments is often limited by inter-individual variability, resources, and appropriate implementation (Dole and Nyswander, 1976; Ward et al., 2009; Kreek et al., 2010). As such, recent approaches have examined allosteric modulators of MOPR and biased signaling mechanisms as a means of offsetting the negative side effects of opioid pain medications (Manglik et al., 2016). A better understanding of how different pain conditions alter MOPR function with consideration of the interplay with ongoing opioid use will aid the development of future pharmacotherapeutic targeting strategies.

κ Opioid receptor

In contrast to the rewarding effects exerted by MOPR activity, the KOPR system is often attributed to dysphoria, anhedonia, and aversion (Spanagel et al., 1992; Darcq and Kieffer, 2018; Liu et al., 2019; Massaly et al., 2019; Cahill et al., 2022b). The opioid peptide, dynorphin, and its activity at KOPR have been implicated in negative affect, pain, analgesia, stress, and addiction (Bruchas et al., 2009; Darcq and Kieffer, 2018). A large body of evidence demonstrates that pain increases dynorphin mRNA expression and peptide production in the spinal cord of rodents and humans (Iadarola et al., 1988; Millan et al., 1988, 1985; Samuelsonn et al., 1993; Xu et al., 2004; Podvin et al., 2016; Liu et al., 2019). Following the onset of pain, the increase in dynorphin parallels the development of hyperalgesia and KOPR antagonism can facilitate hyperalgesic responses (Millan et al., 1987; Xu et al., 2004). This suggests that the dynorphin-kappa system is actively recruited under pain conditions to suppress nociceptive transmission. However, the ability of KOPR activity to suppress hyperalgesic responses may be dependent on the cell populations activated by dynorphin. For example, spinally restricted dynorphin signaling at KOPR expressed in astrocytes, rather than neurons, can produce nociceptive responses (Chartoff and Mavrikaki, 2015; Cahill et al., 2022b). In this regard, astrocytic KOPR activation can trigger hypertrophy in spinal astrocytes to facilitate the persistence of pain and the development of MOPR analgesic tolerance (Donnelly et al., 2020).

Pain can also trigger dynorphin-mediated KOPR activity in supraspinal regions. Pain induced adaptations to KOPR function within mesolimbic pathways may represent a primary mechanism by which pain can lead to the emergence of negative affect and altered motivational states. Indeed, pain conditions increase dynorphin expression and KOPR activity in multiple supraspinal sites including the VTA and NAc (Narita et al., 2005; Tejeda et al., 2017; Liu et al., 2019; Massaly et al., 2019; Navratilova et al., 2019; Wawrzczak-Bargieła et al., 2020). Although genetic deletion of KOPR or KOPR antagonism fails to alter pain-induced hyperalgesia, these manipulations can effectively restore pain-induced anhedonia and aversion (Narita et al., 2005; Tejeda et al., 2017; Liu et al., 2019; Massaly et al., 2019; Navratilova et al., 2019; Vergara et al., 2020). Recent evidence suggests that KOPR activity in NAc may be important for the transition from acute to chronic pain. Using hind paw injections of prostaglandin E2 to induce a persistent hyperalgesic state in rats, KOPR manipulations did not affect mechanical sensitivity during the induction phase (14 daily injections) (Vergara et al., 2020). Rather, intra-NAc KOPR agonists or antagonists facilitated or inhibited the persistence of hyperalgesia, respectively (Vergara et al., 2020). The findings suggest that the KOPR system may play an important role in pain chronification (Borsook et al., 2016).

Dynorphin recruitment under conditions of pain and the ability of KOPR activity to drive the transition from acute to chronic pain, suggest that KOPR may also be important for the development of comorbidities associated with persistent pain states such as negative affect and motivational deficits (Al-Hasani et al., 2015; Hipólito et al., 2015; Taylor et al., 2015; Elman and Borsook, 2016; Liu et al., 2019; Massaly et al., 2019). In general, KOPR agonists produce aversion and are associated with negative affect across species. In humans, KOPR agonists have psychotomimetic effects and produce dysphoria and hallucinations (Pfeiffer et al., 1986; Ranganathan et al., 2012) while increasing circulating stress hormone levels of cortisol (Ur et al., 1997). Similarly, in rodent models, both systemic and intracranial injections of KOPR agonists are sufficient to produce a conditioned place aversion (CPA) (Chefer and Ba, 2013; Tejeda et al., 2013) and increases in circulating levels of the stress hormone, corticosterone (Hayes and Stewart, 1985; Iyengar et al., 1986). These findings indicate that dynorphin-mediated activation of KOPR is acutely aversive and stimulates HPA axis activity, a putative mechanism contributing to negative affect associated with pain conditions. In support of this, increases in NAc dynorphin are found in suicidal individuals (Hurd et al., 1997) and animal models of depression (Carlezon and Krystal, 2016; Tejeda and Bonci, 2019). Importantly, these effects appear to be driven by the ability of KOPR activity to attenuate DA release in the NAc (Chefer and Ba, 2013; Conway et al., 2019; Escobar et al., 2020).

Dynorphin recruitment in mesolimbic pathways under conditions of pain leads to motivational deficits. For example, our lab showed that inflammatory pain increases KOPR function and recruits dynorphin-containing neurons in the NAc shell (Massaly et al., 2019). In this work, we found that the recruitment of NAc shell dynorphin neurons and activity at KOPR is both necessary and sufficient to drive pain-induced motivational deficits for natural rewards (Massaly et al., 2019). These effects also translate to motivational deficits for opioid drug reward. In models of neuropathic or inflammatory pain, morphine-induced conditioned place preference (CPP) scores are attenuated but can be restored by intra-NAc infusions of KOPR antagonists (Narita et al., 2005; Liu et al., 2019). Moreover, pain reduced opioid-evoked DA release in the NAc, an effect restored by intra-systemic KOPR antagonism (Narita et al., 2005; Liu et al., 2019). This suggests that pain-induced recruitment of dynorphin significantly decreases opioid reward processing. Importantly, KOPR antagonism does not impact opioid reward or dopamine release in the absence of pain (Liu et al., 2019), further implicating the state-dependent role of dynorphin. Opioid exposure, in the absence of pain, can perturb KOPR function in a manner similar to pain. For example, opioid self-administration or chronic opioid exposure increases prodynorphin (dynorphin precursor) levels in the NAc (Nylander et al., 1995; Trujillo et al., 1995; Solecki et al., 2009; Schlosburg et al., 2013). Based on this, pain patients on long-term opioid therapies may have compounding effects of pain and opioid use on KOPR dysfunction, exacerbating motivational deficits, negative affect, and leading to increased risk for maladaptive opioid use. Consistent with this idea, genetic polymorphisms to the prodynorphin gene have been linked with increased risk for OUD (Clarke et al., 2012).

The role of the KOPR system in pain-related mood disturbances and negative affect make this system an appealing target from a treatment perspective (Roeckel et al., 2016; Jassar et al., 2019; Llorca-Torralba et al., 2019b). Although systemic KOPR agonists can produce analgesia, many undesirable effects including hallucinations, impaired stress-coping skills, and deficits in reward-driven motivation, limit their clinical utility as therapeutic alternatives to traditional exogenous opioids (Jarcho et al., 2012; Davis et al., 2017; Jones and McCance-Katz, 2019; Toubia and Khalife, 2019; Emery and Akil, 2020). However, pharmacotherapies with partial agonist properties at KOPR have been examined in clinical trials for treatment of alcohol use disorder (AUD). Nalmefene, a MOPR inverse agonist and weak partial KOPR agonist can effectively reduce alcohol consumption and heavy drinking days (Barrio et al., 2018; Miyata et al., 2019), while improving emotional processing in AUD patients (Vollstädt-Klein et al., 2019). On the other hand, considering the upregulated KOPR signaling in supraspinal sites driving negative affective states under pain conditions, the development of KOPR antagonists may yield promising therapeutic potential for the treatment or prevention of neuropsychiatric disorders comorbid with pain (Ghozland et al., 2002; Liu et al., 2019; Escobar et al., 2020; Ji et al., 2021; Cahill et al., 2022b). Buprenorphine is a KOPR antagonist/partial agonist, a partial MOPR and NOPR agonist, and DOPR antagonist with higher efficacy in the periphery than centrally (Bloms-Funke et al., 2000; Lutfy and Cowan, 2004). As such, this treatment provides higher levels of analgesia while sparing many of the negative side-effects associated with traditional opioid medications (Cowan et al., 1977; Lutfy and Cowan, 2004; Koppert et al., 2005; Gudin and Fudin, 2020). The ability of buprenorphine to reduce depressive symptoms has been demonstrated in patients with treatment resistant depression (Karp et al., 2014) and patients with comorbid depression and OUD (Yovell et al., 2016; Ahmadi et al., 2018a). Adding further support to this strategy, buprenorphine is also effective in reducing pain severity in experimentally-induced pain (Koppert et al., 2005) and pain patients (Pergolizzi and Raffa, 2019; Gudin and Fudin, 2020). In patients with OUD and pain symptoms, combinatorial therapeutic approaches with buprenorphine and naloxone can effectively reduce pain severity (Worley et al., 2017, 2015; Shulman et al., 2020). The ability of similar strategies to curb opioid use and craving are less consistent (Blondell et al., 2010; Ahmadi et al., 2018b; Parida et al., 2019). However, evidence suggests that the efficacy of buprenorphine as a substitution therapy for OUD is dependent on the dose and rate of tapering (Walsh et al., 1994; Sturgeon et al., 2020), but concerns remain for the potential for abuse (Cicero et al., 2018). To advance KOPR targeting strategies, it will be critical for future research to dissociate the analgesic properties of spinal KOPR and the emotional component of pain mediated by supraspinal KOPR. Biased ligands and peripherally restricted pharmacotherapeutics targeting KOPR will be important developments for treating the mood disruptions in the context of pain.

δ Opioid receptor

The DOPR system plays an important role in pain, analgesia, and negative affective states (Quirion et al., 2020). Similar to KOPR, the functional role of the DOPR system may be selectively dependent on pain states. In rodent models of inflammatory or neuropathic pain, DOPR expression increases in the dorsal horn of the spinal cord and DRG neurons (Cahill et al., 2003; Morinville et al., 2004a; Kabli and Cahill, 2007). The recruitment of DOPR in pain conditions appears to have an inhibitory influence over nociception because genetic deletion of DOPR, but not MOPR, exacerbates and prolongs thermal and mechanical sensitivity in mice with inflammatory pain (Gavériaux-Ruff et al., 2008). Similarly, conditional knock-out of DOPR in the peripheral nociceptive neurons exacerbates mechanical sensitivity in conditions of inflammatory or neuropathic pain (Gaveriaux-Ruff et al., 2011). Moreover, systemic, or local DOPR agonism effectively reduces mechanical and thermal hyperalgesia in wild-type, but not DOPR knock-out, mice, adding further support to the anti-nociceptive role of DOPR (Gaveriaux-Ruff et al., 2011). Importantly, the role of DOPR in nociception is dependent on the presence of pain. In the absence of pain, DOPR activity has negligible effects on analgesia; but in the presence of neuropathic or inflammatory pain, DOPR agonists can reduce thermal and mechanical pain sensitivity (Cahill et al., 2001; Gendron et al., 2007a,b; Normandin et al., 2013). DOPR agonists have also been shown to attenuate migraine associated-pain in preclinical models via signaling through calcitonin gene-related peptide (Moye et al., 2021). The weak antinociceptive effects of DOPR agonists in pain naïve animals results from low levels of DOPR expression in plasma membrane. In conditions of pain, the density of DOPR increases at the membrane and cell surface in spinal cord regions and DRG neurons (Quirion et al., 2020). The ability of pain to increase DOPR trafficking is a potential cellular mechanism to explain the pain selective analgesic properties of DOPR agonists. DOPR trafficking is controlled by constitutive pathways involving dynamic remodeling of actin filaments of the cytoskeleton (Mittal et al., 2013) or regulated signaling pathways involving G-protein receptor kinases (GRKs) (Quirion et al., 2020), but the precise mechanisms of DOPR trafficking remain unclear. The DOPR system can modulate nociceptive components of pain not only through neuronal mechanisms, but astrocytic mechanisms as well. For example, deletion of astrocytic DOPR decreases cold allodynia in neuropathic pain while mechanical allodynia is not affected (Reiss et al., 2021). In contrast, DOPR activity in somatostatin-expressing neurons of the dorsal horn of the spinal cord can reduce mechanical, but not thermal, sensitivity in neuropathic pain models (Wang et al., 2018). Therefore, DOPR can modulate distinct elements of the nociceptive experience based on their activity in different cellular populations.

The DOPR system has also received a lot of attention for its role in emotional regulation of mood disorders like anxiety and depression. For example, genetic ablation of DOPR or DOPR antagonists has anxiogenic effects in animal models, while DOPR agonists produce opposite effects (Filliol et al., 2000; Saitoh et al., 2005; Narita et al., 2006a,b; Perrine et al., 2006; Bilkei-Gorzo et al., 2007; Chu Sin Chung and Kieffer, 2013). Similarly, DOPR agonists are associated with higher latency for immobility in the forced swim task, a measure of depressive-like behavior in rodent models (Filliol et al., 2000; Jutkiewicz et al., 2006; Torregrossa et al., 2006), suggesting that pain-related recruitment of DOPR may function to offset mood dysregulation in pain. Unlike MOPR, DOPR activity is not rewarding in the absence of pain. DOPR agonists can elicit CPP in mice with peripheral nerve injury, but not sham controls, while DOPR antagonists selectively produce CPA in mice with pain (Cahill et al., 2022a). This demonstrates the pain state-dependent role of DOPR and suggests that DOPR activation acts as negative reinforcer by alleviating pain rather than producing positive reinforcement.

Given the ability of the DOPR system to modulate analgesic responses and negative affect while sparing any properties that may lead to abuse, DOPR have been investigated for their potential role in curbing opioid use (Quirion et al., 2020). Exogenous opioid exposure can regulate DOPR trafficking in a similar way to the induction of pain. For example, morphine exposure increases DOPR expression at the cell surface of DRG or cortical neurons (Cahill et al., 2001; Morinville et al., 2004b; Gendron et al., 2006). DOPR may also play an important role in the development of analgesic tolerance to exogenous opioids because genetic deletion of DOPR or DOPR antagonists can prevent the development of analgesic tolerance to morphine (Zhu et al., 1999; Abul-Husn et al., 2007; Beaudry et al., 2015). However, the role of DOPR in regulating opioid reward is less clear. DOPR knock-out or DOPR antagonists can facilitate morphine-induced locomotor sensitization (Chefer and Shippenberg, 2009; Billa et al., 2010), a measure of drug responsivity manifesting after repeated drug exposures. However, similar DOPR manipulations have been shown to reduce morphine CPP (Chefer and Shippenberg, 2009; le Merrer et al., 2009, 2011; Billa et al., 2010). These effects may not be attributed to reductions in opioid reinforcement, per se, as these manipulations fail to alter morphine self-administration (David et al., 2008; le Merrer et al., 2011). Instead, DOPR may play an important role in drug-cue associated learning.

DOPR signaling is necessary for cued value-based decisions making, particularly within the NAc shell (Laurent et al., 2014, 2012). This effect is driven by distinct anatomical regulation of DA transmission in the NAc by DOPR (Saigusa et al., 2017), such that DOPR agonists in the NAc core increase extracellular DA, while decreasing DA release in the NAc shell (Hirose et al., 2005; Hipólito et al., 2008; Saigusa et al., 2017). Adding another layer of complexity to DOPR-mediated effects on DA release, is that distinct DOPR subtypes (DOPR-1 and DOPR-2) can differentially regulate DA release through their interactions with MOPR. While stimulation of either subtype can have an inhibitory influence over MOPR-mediated slow increases DA release, the precise mechanisms underlying these effects are less clear. For example, stimulation of DOPR-1, not DOPR-2, can activate MOPR causing rapid increases in extracellular DA. However, DOPR agonists can also facilitate DA release independent of MOPR or DOPR, possibly by regulating sodium channel activity (Murakawa et al., 2004; Hirose et al., 2005; Saigusa et al., 2017). In contrast, DOPR-2, not DOPR-1, may play an important role in the development of analgesic tolerance (Beaudry et al., 2015). Future research delineating the precise role of DOPR in mesolimbic circuits will be crucial to exploit on the therapeutic potential of targeting the DOPR system for pain and opioid abuse. Interestingly, gene polymorphisms to the DOPR encoding gene have been linked with increased risk for drug dependence, further strengthening the need for untangling the DOPR system from the behavioral to the genetic level (Zhang et al., 2008; Crist et al., 2013). Moreover, because DOPR agonists have lower abuse liability than MOPR agonists (Stevenson et al., 2005), the DOPR system may represent a useful target for managing pain states during long-term opioid therapy. While the analgesic properties and anxiolytic effects of DOPR agonists are desirable for improving mood states of chronic pain patients, it should be noted that activation of DOPRs can lead to convulsions which may limit their clinical utility (Pradhan et al., 2011). As such, advancing clinical use of DOPR-based ligands will likely be dependent on the development of biased-ligands or dimer-specific drugs capable of DOPR heteromized with other GPCRs (Chu Sin Chung and Kieffer, 2013). Nevertheless, the DOPR system represents a promising target for the development of chronic pain therapies with improved analgesia and minimal unwanted side-effects attributed to traditional opioid medications.

Nociceptin/orphanin FQ opioid receptor

The role of the NOPR system in pain is complex (Toll et al., 2016). In animal models of inflammatory pain, neuropathic pain, and fibromyalgia, NOPR expression and respective endogenous peptide, nociceptin/orphanin FQ (N/OFQ), are upregulated in DRG neurons, spinal tissue, and supraspinal sites (Andoh et al., 1997; Briscini et al., 2002; Dagnino et al., 2019). The ability of NOPR to regulate nociception is related to crosstalk between the NOPR system and stress systems and anatomical distinctions in NOPR function in spinal versus supraspinal sites. Early studies found that intracerebroventricular administration of N/OFQ reduced hot plate and tail flick latencies, suggesting a pro-nociceptive role of supraspinal NOPR activity (Meunier et al., 1995). However, subsequent studies determined that this pro-nociceptive effect was solely related to stress-induced analgesia (Mogil et al., 1996a,b; Morgan, 1997; Rizzi et al., 2001, 2007), a phenomenon triggering the release of endogenous opioids. The pro-nociceptive effects supraspinal N/OFQ are driven partially by antagonistic effects at MOPR, DOPR, and KOPR (Mogil et al., 1996a,b) as well as non-opioid components of stress-induced analgesia (Rizzi et al., 2001). On the contrary, intrathecal administration of N/OFQ produces anti-nociceptive effects and potentiates the effects of morphine (Xu et al., 1996; Yamamoto et al., 1997), indicating the role of NOPR signaling in pain is anatomically specific. Intrathecal administration of N/OFQ or NOPR agonists reduce pain sensitivity in animal models of neuropathic and inflammatory pain (Hao et al., 1998; Ko and Naughton, 2009; Tzschentke et al., 2017). Similar effects are observed with systemic NOPR agonists on mechanical allodynia in preclinical models of cancer-induced bone pain (Sliepen et al., 2021).

NOPR function also varies depending on the persistence of pain. Genetic deletion of NOPR does not alter acute pain sensitivity but exacerbates hyperalgesic responses in conditions of persistent inflammatory pain (Depner et al., 2003; Rizzi et al., 2011). However, significant differences in NOPR supraspinal distribution and localization is observed between species, particularly between preclinical animal models and non-human primates/humans (Florin et al., 2000; Berthele et al., 2003). As such, the effects of NOPR manipulations in preclinical models of pain may not directly translate to clinical populations (Spetea et al., 2022). Because cellular adaptations within the NOPR system and anatomical distribution of NOPR vary across species and different pain models, future research is required to uncover how recruiting/silencing NOPR signaling can efficiently treat pain symptoms in a more individualized setting.

When considering the clinical utility of targeting the NOPR system for treating opioid abuse in pain patients, it is important to highlight that NOPR activity is neither rewarding nor aversive (Devine et al., 1996). This significantly adds to the therapeutic potential of targeting the NOPR system since NOPR manipulations mitigate abuse potential while sparing negative side-effects. NOPR agonists reduce extracellular release of DA in the NAc (Murphy et al., 1996; Lutfy et al., 2001a), suggesting an inhibitory influence of NOPR activity over drug reward. Indeed, intracerebroventricular administration of N/OFQ or NOPR agonists block the acquisition of CPP for morphine, cocaine, alcohol, and methamphetamine (Ciccocioppo et al., 2000; Kotliñska et al., 2002, Kotlinska et al., 2003; Sakoori and Murphy, 2004; Zaveri et al., 2018). This evidence further solidifies the therapeutic potential of the NOPR system in mitigating opioid abuse and substance use disorders in general. Recent studies found that local administration of N/OFQ in the central amygdala attenuates escalation of oxycodone self-administration (Kallupi et al., 2020). These effects may be attributed to site-specific NOPR regulation as intracerebroventricular administration of N/OFQ fails to reduce heroin self-administration (Walker et al., 1998.). Further adding to this complexity is that the effects of NOPR manipulations have inconsistent effects on alcohol self-administration (Ciccocioppo et al., 1999, 2004; Kuzmin et al., 2004; Economidou et al., 2008). One possibility is that NOPR function may be important for drug-associated memory formation given that NOPR activity can negatively impact memory (Moulédous, 2019). In this regard, NOPR activity may impact the formation of drug-context association (conditioned place preference) rather than impact drug reinforcement and thus, instrumental drug-seeking behavior. This would align with findings demonstrating that NOPR agonists effectively block the acquisition of morphine CPP, but not its expression (Shoblock et al., 2005). The precise mechanisms underlying the effects of pain and opioid use on NOPR function remain unclear, but emerging evidence indicates that NOPR agonists, like cebranopadol, have high analgesic efficacy in chronic pain, delayed development of analgesic tolerance, and lower abuse potential (Linz et al., 2014; Tzschentke et al., 2019). Therefore, it will be important for ongoing research endeavors to fully characterize the role of NOPR in the context of pain and opioid misuse liability and determine whether this opioid system is a therapeutic target with clinical utility.

Opioid system dysfunction by exogenous opioids

Chronic exogenous opioid use can lead to the development of tolerance, a progressive decrease in opioid efficacy which can be mitigated by increasing opioid doses (Lee et al., 2011). Pain patients on long-term opioid therapy typically require increasing doses of opioids to achieve the same level of analgesia (Williams et al., 2001; Zernig et al., 2007; Hayes et al., 2020). In addition to analgesia, tolerance to other opioid-induced effects, like euphoria, sedation, nausea, respiratory depression, and constipation, can also develop over time, albeit not at the same rate (Hayhurst and Durieux, 2016). For example, the development of analgesic and euphoric tolerance occurs on a faster time scale than tolerance to respiratory depression (Ling et al., 1989; Volkow et al., 2018), which contributes to the heightened risk of overdose for opioid users with escalating opioid doses (Kaplovitch et al., 2015; Hayes et al., 2019, 2020). Furthermore, the rate at which tolerance develops often depends on genetic variability and differential responses to different opioid ligands, duration of exposure, and route of administration (Dumas and Pollack, 2008; Ballantyne and Koob, 2021).

Tolerance

The development of tolerance stems from desensitization of the opioid system and inflammatory immune responses within peripheral and central nervous systems (Zhu et al., 1999; Dumas and Pollack, 2008; Koch and Höllt, 2008; Matsui et al., 2014; Corder et al., 2017; Lueptow et al., 2018; Eidson and Murphy, 2019). Following activation, opioid receptors can be phosphorylated by GPCR kinases, which triggers G-protein uncoupling and binding of β-arrestins (Dumas and Pollack, 2008; Zhou et al., 2021). β-arrestin pathway signaling causes desensitized receptors to remain inactive at the plasma membrane, facilitates their endocytosis and subsequent degradation or recycling. As such, these cellular mechanisms represent a critical component in facilitating the development of tolerance at multiple levels (Hutchings et al., 1997; Bohn et al., 2000; Koch and Höllt, 2008; Zhou et al., 2021). Biased agonists, that preferentially activate G-protein signaling cascades with minimal β-arrestin pathway activity, have received great interest as therapeutic alternatives with the thought that such ligands may minimize the development of tolerance and other unwanted side-effects (Ballantyne and Chavkin, 2020). In mice with genetic deletion of the β-arrestin2 isoform, acute morphine prolongs analgesia while reducing the unwanted side-effects of respiratory depression and constipation, while chronic morphine treatment reduces MOPR desensitization and the development of tolerance (Bohn et al., 1999, 2000; Raehal et al., 2011). These findings led to the development of functionally selective MOPR agonists, like oliceridine, which exhibit preference for G protein-biased signaling and produce less respiratory depression in preclinical models compared to non-selective agonists (DeWire et al., 2013). However, subsequent studies found that opioid-induced respiratory depression and constipation may occur independent of β-arrestins (Kliewer et al., 2020) and G-protein selectivity may worsen some side effects (Kliewer et al., 2019). Although negative side-effects remained during clinical trials (Hertz, 2018), the risk for respiratory depression with oliceridine was lower than morphine (Dahan et al., 2020). Similar findings were found for another biased-MOPR agonist, PZM21 (Graeme Henderson et al., 2018), further highlighting the need to better understand biased opioid ligand signaling mechanisms and their role tolerance.

NOPR signaling appears to play facilitative role in the development of tolerance in the context of pain. As previously mentioned, NOPR expression increases after the induction of pain in spinal and supraspinal sites (Andoh et al., 1997; Briscini et al., 2002; Dagnino et al., 2019) which, under conditions of chronic pain, can suppress hyperalgesic responses (Depner et al., 2003; Rizzi et al., 2011). Based on this, it is somewhat surprising that N/OFQ potentiates the development of opioid tolerance. Genetic ablation of the endogenous peptide, nociceptin, N/OFQ, its receptor (NOPR), or blocking NOPR signaling using an exogenous antagonist, prevents and reverses the development of morphine tolerance (Ueda et al., 1997; Lutfy et al., 2001b; Chung et al., 2006; Scoto et al., 2010). These likely are attributed to the antagonistic properties of N/OFQ at other opioid receptors (Mogil et al., 1996b). NOPR can also undergo desensitization after chronic or acute stimulation (Donica et al., 2013). While these findings suggest that pain-induced upregulation of the NOPR system underlies attenuated analgesic responses to exogenous opioids, they also suggest that targeting the NOPR system may be a useful target to treat vulnerabilities in opioid tolerance, escalation, and abuse in pain patients.

The development of tolerance can also develop in response to the recruitment of neuroinflammatory mediators. Long-term opioid use triggers neuroinflammatory responses in the CNS to increase neuronal excitability which can contribute to tolerance (Eidson and Murphy, 2019; Zhang et al., 2020; Zhou et al., 2021). In particular, the ventrolateral PAG (vlPAG) is a critical hub in which descending control over nociceptive signaling is negatively affected by chronic opioid use. Chronic intra-vlPAG opioid agonist administration is sufficient to produce tolerance to systemically administered opioids. Similarly, blocking vlPAG opioid receptor-mediated signaling can prevent the development of tolerance to chronic systemic administration of exogenous opioids (Lane et al., 2004; Morgan et al., 2006; Meyer et al., 2007; Loyd et al., 2008; Macey et al., 2009; Bobeck et al., 2012; Eidson and Murphy, 2019). Opioid-induced activation of toll-like receptor 4 (TLR4) in astrocytes and microglia within the spinal cord or PAG triggers inflammatory responses through activation of nuclear factor kappa B (NFκB) and the release of pro-inflammatory cytokines such as tumor necrosis factor α (TNFα) and interleukins, IL-1β and IL-6 (Raghavendra et al., 2002; Eidson et al., 2016; Liang et al., 2016; Eidson and Murphy, 2019; Wang et al., 2020). This release in cytokines leads to down-regulation of GABA receptors resulting in increased function of glutamate receptor systems. Consequently, hyper-excitability in nociceptive pathways acts to oppose the analgesic actions of opioids, resulting in tolerance (DeLeo et al., 2004; Eidson and Murphy, 2019; Zhou et al., 2021). Based on the role of cytokines in opioid tolerance, significant efforts have been directed toward the development of treatments that may inhibit opioid-induced cytokine production (Namba et al., 2021). For example, manipulations inhibiting TNF signaling through TLR4 can prevent morphine tolerance and associated hyperexcitability (Shen et al., 2011; Eidson et al., 2016; Wang et al., 2020). As such, modulation of TNF signaling represents a promising adjunctive therapy to curb the development of opioid tolerance. Taken together, opioid tolerance manifests through adaptations to endogenous opioid and inflammatory systems, but a better understanding of the relationship between these systems will facilitate our ability to identify novel therapeutic targets to overcome the development of opioid tolerance.

Opioid-induced hyperalgesia

In contrast to the development of tolerance, chronic opioid use can also result in opioid-induced hyperalgesia (OIH), a paradoxical increase in pain sensitivity either at the initial source of pain or elsewhere (Chu et al., 2008; Hay et al., 2009; Roeckel et al., 2016). While the phenomenon of tolerance represents a reduction in drug potency and creates a rightward shift in analgesic opioid dose response curves, OIH increases pain sensitivity modeled by a significant downward shift in analgesic dose response (Chu et al., 2008). It is, thus, distinct from tolerance in that escalating opioid doses may exacerbate the development of OIH in the long-term. However, both tolerance and OIH are associated with hyperexcitability in glutamatergic systems and up-regulation of pro-inflammatory molecules at spinal synapses and supraspinal regions, like the RVM (Bederson et al., 1990; Kaplan and Fields, 1991; Kovelowski et al., 2000; Vanderah et al., 2001). OIH is a pro-nociceptive process that can be observed independently of tolerance through acute exposure to ultra-low opioid doses. However, the development of OIH is more often observed after the development of tolerance, following chronic exposure to higher, analgesic doses (Drdla et al., 2009; Silverman, 2009; Lee et al., 2011; Hayhurst and Durieux, 2016; Roeckel et al., 2016).

Opioid-induced hyperalgesia is driven by cellular adaptations in pronociceptive signaling pathways, particularly within glutamatergic systems (Lee et al., 2011). Opioid agonists increase cellular excitability underlying OIH by inhibiting glutamate transporter systems (Mao et al., 2002). The resulting abundance in synaptic glutamate can lead to NMDA receptor-dependent long-term potentiation (LTP) at primary afferents and second-order spinal neurons resulting in sensitization of pain signaling pathways (Drdla et al., 2009; Silverman, 2009; Heinl et al., 2011; Drdla-Schutting et al., 2012; Roeckel et al., 2016; Corder et al., 2018). Adding to this, previous reports from our lab found that OIH is driven by insertion of GluA4-containing AMPA receptors in the dorsal horn of the spinal cord (Cabañero et al., 2013). Similar to the development of tolerance, OIH is also associated with opioid-dependent production and release of nociceptive signaling molecules from microglia and astrocytes such as pro-inflammatory cytokines, chemokines, ATP, nitric oxide, and others detailed elsewhere (Chu et al., 2008; Lee et al., 2011; Roeckel et al., 2016). Consequent release of the neuropeptide, cholecystokinin (CCK) in the RVM has been shown to have ‘anti-opioid’ actions that facilitate pronociceptive pathways contributing to OIH (Kaplan and Fields, 1991; Kovelowski et al., 2000; Friedrich and Gebhart, 2003; Heinricher and Neubert, 2004). The NMDA receptor-dependent hyperexcitability associated with OIH has been targeted in efforts to mitigate the impact of opioids on central sensitization. For example, low-dose ketamine (non-selective NMDA receptor antagonist) administration in conjunction with opioid analgesics can prevent the development of OIH in animal models and clinical patients with postoperative pain (Célèrier et al., 2000; Maher et al., 2017). Similarly, methadone, a potent MOPR agonist and weak NMDA receptor antagonist, has been examined as a substitute for opioid therapies and can effectively reduce opioid-induced OIH (Sjøgren et al., 1994; Shimoyama et al., 1997; Davis and Inturrisi, 1999; Axelrod and Reville, 2007). While the efficacy of methadone maintenance treatment (MMT) is less reliable in patients with opioid dependence or a prior history of abuse, MMT reduce instances of heroin use, drug craving, and criminal activity (Dole and Nyswander, 1965, 1976; Shi et al., 2008; Mattick et al., 2009; Ward et al., 2009; Lee et al., 2011). Despite this, moral reservations among some groups precipitated shifts in the treatment goals initially outlined for long-term MMT advising sufficient dosing and instead, goals were centered around achieving abstinence and using less-than-effective doses, which compromised treatment outcomes and funding for MMT research (Dole and Nyswander, 1976; Ward et al., 2009). As such, OIH remains a barrier to effective treatment with opioids. Further research delineating the mechanisms mediating the physiological and behavioral effects of opioids and whether pain affects these properties will help facilitate the development of novel and safer pharmacotherapies to improve patient care and well-being.

Pain, opioids, and reward

The mesolimbic pathway integrates both aversive and rewarding properties of external stimuli (Bromberg-Martin et al., 2010). Activation of the mesolimbic pathway by rewarding stimuli results in phasic DA release from the VTA into the NAc to reinforce goal-directed behaviors (Fibiger et al., 1987; Berridge and Robinson, 1998; Becerra and Borsook, 2008; Pignatelli and Bonci, 2015). As described previously, opioids reliably activate mesolimbic DA pathway and thus promote motivational salience (Matsui et al., 2014; Galaj et al., 2020; Doyle and Mazei-Robison, 2021). In conditions of pain, the ability of opioids to trigger comparable responses is significantly reduced. Furthermore, the motivational salience of opioid reward may be driven by hedonic pleasure (positive reinforcement) or pain relief (negative reinforcement) (Koob, 2020). Similar to exogenous opioids in pain-naïve conditions, relief from pain itself can elicit increases in DA release and reinforce motivated behaviors (Martin et al., 2006; Leknes et al., 2011; Navratilova et al., 2015; Eikemo et al., 2021). As such, the presence of pain may perpetuate maladaptive patterns of opioid use.

Pain disrupts mesolimbic DA function contributing to maladaptive effects on reward processing. Deficits in DA signaling, or administration of DA receptor antagonists reduce approach behaviors and hedonic responses to rewarding stimuli (Frank et al., 2016; Nguyen et al., 2019). In rodent models of inflammatory and nerve injury pain, motivated behaviors for natural and drug rewards, such as opioids, are significantly impaired (Schwartz et al., 2014; Hipólito et al., 2015; Taylor et al., 2015; Massaly et al., 2019). This pain-induced decrease in motivation is strongly correlated with blunted DA signaling in the mesolimbic pathway (Cahill et al., 2013; Schwartz et al., 2014; Hipólito et al., 2015). These findings parallel clinical studies in which pain-induced negative emotional states positively correlates with reductions in DA neurotransmission and maladaptive changes in NAc function (Lee and Tracey, 2010; Jarcho et al., 2012; Martikainen et al., 2015; Makary et al., 2020). Importantly, pain-related alterations in DA signaling are also associated with deficits in emotional and sensory processing. For example, deficits in DA receptor binding potential in the NAc are observed in patients with lower back pain, which can predict the severity of negative affect and pain (Baliki et al., 2010; Martikainen et al., 2015). In line with this, DA transporter activity, a mechanism important for clearing DA from the synaptic cleft, is increased in the NAc of animal models of chronic neuropathic or inflammatory pain (Ren et al., 2015, 2021; Selley et al., 2020). Moreover, morphine-induced DA release in the NAc is suppressed by sciatic nerve ligation (Niikura et al., 2008). These changes in mesolimbic DA function strongly impact reward thresholds which may contribute to pain-related occurrences of negative affect and enhanced vulnerability for opioid abuse (Massaly et al., 2019, 2021). Supporting this, pain patients are more likely to initiate and continue opioid treatment if they have a cooccurring mood disorder (Halbert et al., 2016).

Opioid abuse susceptibility in pain states is likely exacerbated by a rightward shift in opioid reinforcement thresholds due to pain-related deficits in mesolimbic pathway function. In lower back pain patients, the propensity for risky monetary behavior is associated with altered connectivity of the NAc (Berger et al., 2014). The severity of pain is also associated with increased impulsivity in humans and rodent models (Wakaizumi et al., 2019; Cunha et al., 2020). These would suggest that pain patients are predisposed to developing problematic opioid use. Although it is recognized that chronic pain patients receiving prescription opioids are at high risk for opioid dependence (Ballantyne, 2015), the prevalence of maladaptive opioid use in pain patients has been difficult to determine based on confounding outcome measurements (i.e., mortality) and imprecise or poorly defined terminology (i.e., “abuse,” “misuse,” “addiction”) (Vowles et al., 2015). Opioid “misuse,” or use contrary to the prescribed pattern, occurs in up to 29% of pain patients receiving opioid medications while “addiction,” or continued use despite negative consequences, can occur in up to 12% (Vowles et al., 2015). Opioid “abuse,” or aberrant drug taking behavior often predictive of maladaptive opioid use has been reported in 46–81% of pain populations (Butler et al., 2004; Wilsey et al., 2008; Vowles et al., 2015). However, there remains a general consensus that high-quality research on this relationship is lacking (Ballantyne, 2015; Voon et al., 2017; Nadeau et al., 2021). Nevertheless, qualitative evidence from clinical literature indicates that negative outcomes associated with opioid use can be instigated by pain severity (Grol-Prokopczyk, 2017; Zajacova et al., 2021), duration of opioid use (Chung et al., 2019; Jantarada et al., 2021), escalating opioid doses (Zernig et al., 2007; Kaplovitch et al., 2015), comorbid anxiety and depression (Peciña et al., 2018; Emery and Akil, 2020; Rogers et al., 2020), discontinuation of opioid medications (Mark and Parish, 2019; Stein et al., 2021), and inherent risk factors like sex (Manubay et al., 2015; McHugh, 2020) or genetics (Kendler et al., 2003; Agarwal et al., 2017). Evidence from patients with pain and long-term opioid use have been critical in identifying potential risk factors for maladaptive opioid use but have yielded minimal impacts on either public health concern.

Determining the level of synergy between pain, long-term opioid use, and opioid misuse can be difficult for many reasons, but preclinical pain models of opioid self-administration provide a translational means to better understand how pain may provoke motivational shifts to alter opioid misuse liability. Although pain-induced dysfunction of mesolimbic reward pathways produces clear deficits in motivation for natural rewards (Massaly et al., 2019, 2021; Reiner et al., 2019), the effects of pain on opioid motivation are more complex. Evidence from self-administration studies suggest that the ability of pain to effect opioid self-administration is related to the chronicity of pain, selected opioid/dose, and the duration of daily opioid exposure. For example, chronic arthritic pain has biphasic effects on rates of oral fentanyl self-administration, that interestingly, follow the time-course of pain progression (Colpaert et al., 2001, 1982). Specifically, one week after the onset of pain there are no effects on fentanyl consumption but, during successive weeks, fentanyl intake dramatically increases—peaking at 2–3 weeks – and declines to baseline levels several weeks later. Importantly, the time course of fentanyl consumption rates parallels the time course of progressive pain sensitivity (Colpaert et al., 1982, 2001). Similarly, spinal cord injury has time-dependent effects on long-access morphine self-administration in rats. In this regard, pain reduces morphine intake 24 h after the induction of pain, then peaks at 14–21 days before normalizing 35–42 days later (Woller et al., 2014). These findings indicate that the persistence of pain is an important driver of opioid consumption. Adding further support to this, acute pain manipulations with capsaicin or lactic acid do not alter rates of fentanyl or heroin self-administration, but persistent inflammatory pain-induced reductions in fentanyl vs. food choice procedures match controls by one week after the induction of pain (Reiner et al., 2021). Notably, a small study found that arthritic pain reduced self-administration of relatively high doses of morphine with 24-h access for weeks following pain onset (Lyness et al., 1989) while another found that multiple forms of chronic pain attenuated oral fentanyl self-administration and discrimination in mice (Wade et al., 2013). These findings allude to the notion that pain may produce a shift opioid dose-response. Consistent with this, our lab found that inflammatory pain reduces heroin intake at low doses, but increases intake when doses are high (Hipólito et al., 2015). Our findings suggest that these effects are driven by deficits in VTA DA cell excitability (Hipólito et al., 2015) and this is exemplified by evidence showing that pain reduces the ability of low-dose opioids to facilitate VTA intracranial self-stimulation (Ewan and Martin, 2011). Spinal nerve ligation also produces a rightward shift in dose-response for multiple opioids, but the time-dependency of these effects has not been examined (Martin et al., 2007). Taken together, evidence from preclinical pain models of opioid abuse suggest that chronic pain can increase motivation for high opioid doses in a time-dependent manner that parallels the progression of pain. It will be important for future studies to evaluate whether the time- and dose-dependent effects of pain on opioid consumption are related to time-dependent disruptions in mesolimbic pathway function.

Conclusions

Pain conditions, chronic opioid use, and withdrawal from chronic opioid use disrupt the endogenous opioid system function at spinal and supraspinal levels to negatively impact pain thresholds, opioid sensitivity, mood, and reward sensitivity. These physiological and behavioral alterations, particularly among opioid systems and mesolimbic reward pathways, may contribute to persistent use of opioid medications in an attempt to alleviate adverse physical and emotional states, thereby creating a susceptibility for opioid misuse. In addition, other mediating factors outside the scope of this review contribute to individual variabilities in pain perception and opioid sensitivity like sex differences (Huhn et al., 2018; Pisanu et al., 2019), genetic (Tremblay and Hamet, 2010; Mogil, 2012), and epigenetic mechanisms (Liang et al., 2015; Browne et al., 2019) and likely influence proclivity for opioid abuse in the context of pain. Neuroadaptive processes produced by pain conditions and long-term opioid use have compounding effects on negative outcomes, like the development of tolerance or opioid-induced hyperalgesia. An understanding of the synergy between these processes remains incomplete, but the ability to curb the opioid crisis and the prevalence of pain relies heavily on the ability to identify safer pharmacotherapeutic alternatives derived from a better comprehension of pain- and opioid-induced adaptations to opioid systems and functional neurocircuitry.

Author contributions

All authors contributed to the format and writing of the review and approved the final submitted version.

Funding

This work was supported by US National Institutes of Health (NIH) [grants DA726129 (JH), DA041781 (JM), DA042581 (JM), DA042499 (JM), DA041883 (JM), and DA045463 (JM)], W. M. Keck Fellowship (JH), and NARSAD Independent Investigator Award from the Brain and Behavior Research Foundation (JM).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

Abul-Husn, N. S., Sutak, M., Milne, B., and Jhamandas, K. (2007). Augmentation of spinal morphine analgesia and inhibition of tolerance by low doses of mu- and delta-opioid receptor antagonists. Br. J. Pharmacol. 151, 877–887. doi: 10.1038/SJ.BJP.0707277

PubMed Abstract | CrossRef Full Text | Google Scholar

Agarwal, D., Udoji, M. A., and Trescot, A. (2017). Genetic testing for opioid pain management: a primer. Pain Ther. 6, 93–105. doi: 10.1007/S40122-017-0069-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Ahmad, F., Rossen, L., and Sutton, P. (2022). Provisional Drug Overdose Death Counts. Hyattsville, MD: National Center for Health Statistics.

Google Scholar

Ahmadi, J., Jahromi, M. S., and Ehsaei, Z. (2018a). The effectiveness of different singly administered high doses of buprenorphine in reducing suicidal ideation in acutely depressed people with co-morbid opiate dependence: a randomized, double-blind, clinical trial. Trials 19, 1–8. doi: 10.1186/s13063-018-2843-9

PubMed Abstract | CrossRef Full Text | Google Scholar

Ahmadi, J., Jahromi, M. S., Ghahremani, D., and London, E. D. (2018b). Single high-dose buprenorphine for opioid craving during withdrawal. Trials 19, 1–7. doi: 10.1186/S13063-018-3055-Z/TABLES/4

CrossRef Full Text | Google Scholar

Al-Hasani, R., and Bruchas, M. R. (2011). Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology 115, 1363–1381. doi: 10.1097/ALN.0B013E318238BBA6

PubMed Abstract | CrossRef Full Text | Google Scholar

Al-Hasani, R., McCall, J. G., Shin, G., Gomez, A. M., Schmitz, G. P., Bernardi, J. M., et al. (2015). Distinct subpopulations of nucleus accumbens dynorphin neurons drive aversion and reward. Neuron 87, 1063–1077.

Google Scholar

Andoh, T., Itoh, M., and Kuraishi, Y. (1997). Nociceptin gene expression in rat dorsal root ganglia induced by peripheral inflammation. Neuroreport 8, 2793–2796. doi: 10.1097/00001756-199708180-00028

PubMed Abstract | CrossRef Full Text | Google Scholar

Axelrod, D. J., and Reville, B. (2007). Using methadone to treat opioid-induced hyperalgesia and refractory pain. J. Opioid Manag. 3, 113–114. doi: 10.5055/JOM.2007.0048

PubMed Abstract | CrossRef Full Text | Google Scholar

Baliki, M. N., Geha, P. Y., Fields, H. L., and Apkarian, A. V. (2010). Predicting value of pain and analgesia: nucleus accumbens response to noxious stimuli changes in the presence of chronic pain. Neuron 66, 149–160. doi: 10.1016/J.NEURON.2010.03.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Ballantyne, J. C. (2015). Assessing the prevalence of opioid misuse, abuse, and addiction in chronic pain. Pain 156, 567–568. doi: 10.1097/J.PAIN.0000000000000105

PubMed Abstract | CrossRef Full Text | Google Scholar

Ballantyne, J. C., and Chavkin, C. (2020). Will biased ligands be the opioids of the future? Pain 161, 1945–1948. doi: 10.1097/J.PAIN.0000000000001913

PubMed Abstract | CrossRef Full Text | Google Scholar

Ballantyne, J. C., and Koob, G. F. (2021). Allostasis theory in opioid tolerance. Pain 162, 2315–2319. doi: 10.1097/J.PAIN.0000000000002280

PubMed Abstract | CrossRef Full Text | Google Scholar

Ballester, J., Baker, A. K., Martikainen, I. K., Koppelmans, V., Zubieta, J. K., and Love, T. M. (2022). Risk for opioid misuse in chronic pain patients is associated with endogenous opioid system dysregulation. Transl. Psychiatry 12, 1–7. doi: 10.1038/s41398-021-01775-z

PubMed Abstract | CrossRef Full Text | Google Scholar

Bannister, K., and Dickenson, A. H. (2020). Central nervous system targets: supraspinal mechanisms of analgesia. Neurotherapeutics 17, 839–845. doi: 10.1007/S13311-020-00887-6

PubMed Abstract | CrossRef Full Text | Google Scholar

Barrio, P., Ortega, L., Guardia, J., Roncero, C., Yuguero, L., and Gual, A. (2018). Who receives nalmefene and how does it work in the real world? A single-arm, phase iv study of nalmefene in alcohol dependent outpatients: baseline and 1-month results. Clin. Drug Investig. 38, 147–155. doi: 10.1007/S40261-017-0590-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Basbaum, A. I., and Fields, H. L. (1984). Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annu. Rev. Neurosci. 7, 309–338. doi: 10.1146/ANNUREV.NE.07.030184.001521

PubMed Abstract | CrossRef Full Text | Google Scholar

Beaudry, H., Gendron, L., and Morón, J. A. (2015). Implication of delta opioid receptor subtype 2 but not delta opioid receptor subtype 1 in the development of morphine analgesic tolerance in a rat model of chronic inflammatory pain. Eur. J. Neurosci. 41, 899–905. doi: 10.1111/ejn.12829

PubMed Abstract | CrossRef Full Text | Google Scholar

Becerra, L., and Borsook, D. (2008). Signal valence in the nucleus accumbens to pain onset and offset. Eur. J. Pain 12, 866–869. doi: 10.1016/J.EJPAIN.2007.12.007

PubMed Abstract | CrossRef Full Text | Google Scholar

Beckett, A. H., and Casy, A. F. (1954). Synthetic analgesics: stereochemical considerations. J. Pharm. Pharmacol. 6, 986–1001. doi: 10.1111/J.2042-7158.1954.TB11033.X

PubMed Abstract | CrossRef Full Text | Google Scholar

Bederson, J. B., Fields, H. L., and Barbaro, N. M. (1990). Hyperalgesia during naloxone-precipitated withdrawal from morphine is associated with increased on-cell activity in the rostral ventromedial medulla. Somatosens. Mot. Res. 7, 185–203. doi: 10.3109/08990229009144706

PubMed Abstract | CrossRef Full Text | Google Scholar

Bencherif, B., Fuchs, P. N., Sheth, R., Dannals, R. F., Campbell, J. N., and Frost, J. J. (2002). Pain activation of human supraspinal opioid pathways as demonstrated by [11C]-carfentanil and positron emission tomography (PET). Pain 99, 589–598. doi: 10.1016/S0304-3959(02)00266-X

CrossRef Full Text | Google Scholar

Berger, S. E., Baria, A. T., Baliki, M. N., Mansour, A., Herrmann, K. M., Torbey, S., et al. (2014). Risky monetary behavior in chronic back pain is associated with altered modular connectivity of the nucleus accumbens. BMC Res. Notes 7:739. doi: 10.1186/1756-0500-7-739

PubMed Abstract | CrossRef Full Text | Google Scholar

Berridge, K. C., and Robinson, T. E. (1998). What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res. Rev. 28, 309–369. doi: 10.1016/S0165-0173(98)00019-8

CrossRef Full Text | Google Scholar

Berthele, A., Platzer, S., Dworzak, D., Schadrack, J., Mahal, B., Büttner, A., et al. (2003). [3H]-nociceptin ligand-binding and nociceptin opioid receptor mrna expression in the human brain. Neuroscience 121, 629–640. doi: 10.1016/S0306-4522(03)00484-6

CrossRef Full Text | Google Scholar

Bilkei-Gorzo, A., Michel, K., Noble, F., Roques, B. P., and Zimmer, A. (2007). Preproenkephalin knockout mice show no depression-related phenotype. Neuropsychopharmacology 32, 2330–2337. doi: 10.1038/SJ.NPP.1301370

PubMed Abstract | CrossRef Full Text | Google Scholar

Billa, S. K., Xia, Y., and Morón, J. A. (2010). Disruption of morphine-conditioned place preference by a delta2-opioid receptor antagonist: study of mu-opioid and delta-opioid receptor expression at the synapse. Eur. J. Neurosci. 32, 625–631. doi: 10.1111/J.1460-9568.2010.07314.X

PubMed Abstract | CrossRef Full Text | Google Scholar

Bloms-Funke, P., Gillen, C., Schuettler, A. J., and Wnendt, S. (2000). Agonistic effects of the opioid buprenorphine on the nociceptin/OFQ receptor. Peptides 21, 1141–1146. doi: 10.1016/S0196-9781(00)00252-7

CrossRef Full Text | Google Scholar

Blondell, R. D., Ashrafioun, L., Dambra, C. M., Foschio, E. M., Zielinski, A. L., and Salcedo, D. M. (2010). A clinical trial comparing tapering doses of buprenorphine with steady doses for chronic pain and coexistent opioid addiction. J. Addict. Med. 4, 140–146. doi: 10.1097/ADM.0b013e3181ba895d

PubMed Abstract | CrossRef Full Text | Google Scholar

Bobeck, E. N., Haseman, R. A., Hong, D., Ingram, S. L., and Morgan, M. M. (2012). Differential development of antinociceptive tolerance to morphine and fentanyl is not linked to efficacy in the ventrolateral periaqueductal gray of the rat. J. Pain 13, 799–807. doi: 10.1016/J.JPAIN.2012.05.005

PubMed Abstract | CrossRef Full Text | Google Scholar

Bodnar, R. J. (2021). Endogenous opiates and behavior: 2019. Peptides 141:170547. doi: 10.1016/J.PEPTIDES.2021.170547

PubMed Abstract | CrossRef Full Text | Google Scholar

Bohn, L. M., Gainetdinov, R. R., Lin, F. T., Lefkowitz, R. J., and Caron, M. G. (2000). μ-Opioid receptor desensitization by β-arrestin-2 determines morphine tolerance but not dependence. Nature 408, 720–723. doi: 10.1038/35047086

PubMed Abstract | CrossRef Full Text | Google Scholar

Bohn, L. M., Lefkowitz, R. J., Gainetdinov, R. R., Peppel, K., Caron, M. G., and Lin, F. T. (1999). Enhanced morphine analgesia in mice lacking β-arrestin 2. Science 286, 2495–2498. doi: 10.1126/science.286.5449.2495

PubMed Abstract | CrossRef Full Text | Google Scholar

Borsook, D., Linnman, C., Faria, V., Strassman, A. M., Becerra, L., and Elman, I. (2016). Reward deficiency and anti-reward in pain chronification. Neurosci. Biobehav. Rev. 68, 282–297. doi: 10.1016/J.NEUBIOREV.2016.05.033

PubMed Abstract | CrossRef Full Text | Google Scholar

Bourinet, E., Soong, T. W., Stea, A., and Snutch, T. P. (1996). Determinants of the G protein-dependent opioid modulation of neuronal calcium channels. Proc. Natl. Acad. Sci. U.S.A. 93, 1486–1491. doi: 10.1073/pnas.93.4.1486

PubMed Abstract | CrossRef Full Text | Google Scholar

Briscini, L., Corradini, L., Ongini, E., and Bertorelli, R. (2002). Up-regulation of ORL-1 receptors in spinal tissue of allodynic rats after sciatic nerve injury. Eur. J. Pharmacol. 447, 59–65. doi: 10.1016/s0014-2999(02)01833-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Bromberg-Martin, E. S., Matsumoto, M., and Hikosaka, O. (2010). Dopamine in motivational control: rewarding, aversive, and alerting. Neuron 68, 815–834. doi: 10.1016/J.NEURON.2010.11.022

PubMed Abstract | CrossRef Full Text | Google Scholar

Bronstein, D. M., Przewlocki, R., and Akil, H. (1990). Effects of morphine treatment on pro-opiomelanocortin systems in rat brain. Brain Res. 519, 102–111. doi: 10.1016/0006-8993(90)90066-K

CrossRef Full Text | Google Scholar

Browne, C. J., Godino, A., Salery, M., and Nestler, E. J. (2019). Epigenetic mechanisms of opioid addiction. Biol. Psychiatry 87, 22–33. doi: 10.1016/j.biopsych.2019.06.027

PubMed Abstract | CrossRef Full Text | Google Scholar

Brownstein, M. J. (1993). Review A brief history of opiates, opioid peptides, and opioid receptors. Proc. Natl. Acad. Sci. U.S.A. 90, 5391–5393. doi: 10.1073/pnas.90.12.5391

PubMed Abstract | CrossRef Full Text | Google Scholar

Bruchas, M. R., Land, B. B., and Chavkin, C. (2009). The dynorphin / kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res. 1314, 44–55. doi: 10.1016/j.brainres.2009.08.062

PubMed Abstract | CrossRef Full Text | Google Scholar

Bruehl, S., Burns, J. W., Chung, O. Y., and Chont, M. (2012). What do plasma beta-endorphin levels reveal about endogenous opioid analgesic function? Eur. J. Pain 16, 370–380. doi: 10.1002/j.1532-2149.2011.00021.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Bruehl, S., Burns, J. W., Gupta, R., Buvanendran, A., Chont, M., Kinner, E., et al. (2013). Endogenous opioid function mediates the association between laboratory-evoked pain sensitivity and morphine analgesic responses. Pain 154, 1856–1864. doi: 10.1016/J.PAIN.2013.06.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Bruehl, S., Burns, J. W., Gupta, R., Buvanendran, A., Chont, M., Orlowska, D., et al. (2017). Do Resting Plasma β-endorphin levels predict responses to opioid analgesics? Clin. J. Pain 33, 12–20. doi: 10.1097/AJP.0000000000000389

PubMed Abstract | CrossRef Full Text | Google Scholar

Bruehl, S., Burns, J. W., Gupta, R., Buvanendran, A., Chont, M., Schuster, E., et al. (2014). Endogenous opioid inhibition of chronic low back pain influences degree of back pain relief following morphine administration. Reg. Anesth. Pain Med. 39:120. doi: 10.1097/AAP.0000000000000058

PubMed Abstract | CrossRef Full Text | Google Scholar

Bunzow, J. R., Saez, C., Mortrud, M., Bouvier, C., Williams, J. T., Low, M., et al. (1994). Molecular cloning and tissue distribution of a putative member of the rat opioid receptor gene family that is not a μ, δ or κ opioid receptor type. FEBS Lett. 347, 284–288. doi: 10.1016/0014-5793(94)00561-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Burford, N. T., Traynor, J. R., and Alt, A. (2015). Positive allosteric modulators of the μ-opioid receptor: a novel approach for future pain medications. Br. J. Pharmacol. 172, 277–286. doi: 10.1111/BPH.12599

PubMed Abstract | CrossRef Full Text | Google Scholar

Butler, S. F., Budman, S. H., Fernandez, K., and Jamison, R. N. (2004). Validation of a screener and opioid assessment measure for patients with chronic pain. Pain 112, 65–75. doi: 10.1016/J.PAIN.2004.07.026

PubMed Abstract | CrossRef Full Text | Google Scholar

Cabañero, D., Baker, A., Zhou, S., Hargett, G. L., Irie, T., Xia, Y., et al. (2013). Pain after discontinuation of morphine treatment is associated with synaptic increase of GluA4-containing AMPAR in the dorsal horn of the spinal cord. Neuropsychopharmacology 38, 1472–1484. doi: 10.1038/npp.2013.46

PubMed Abstract | CrossRef Full Text | Google Scholar

Cahill, C. M., Holdridge, S. V., Liu, S., Xue, L., Magnussen, C., Ong, E., et al. (2022a). Delta opioid receptor activation modulates affective pain and modality-specific pain hypersensitivity associated with chronic neuropathic pain. J. Neurosci. Res. 100, 129–148. doi: 10.1002/JNR.24680

PubMed Abstract | CrossRef Full Text | Google Scholar

Cahill, C. M., Lueptow, L., Kim, H., Shusharla, R., Bishop, A., and Evans, C. J. (2022b). Kappa opioid signaling at the crossroads of chronic pain and opioid addiction. Handb. Exp. Pharmacol. 271, 315–350. doi: 10.1007/164_2021_434

CrossRef Full Text | Google Scholar

Cahill, C. M., Morinville, A., Hoffert, C., O’Donnell, D., and Beaudet, A. (2003). Up-regulation and trafficking of δ opioid receptor in a model of chronic inflammation: implications for pain control. Pain 101, 199–208. doi: 10.1016/S0304-3959(02)00333-0

CrossRef Full Text | Google Scholar

Cahill, C. M., Morinville, A., Lee, M. C., Vincent, J. P., Collier, B., and Beaudet, A. (2001). Prolonged morphine treatment targets δ opioid receptors to neuronal plasma membranes and enhances δ-mediated antinociception. J. Neurosci. 21, 7598–7607. doi: 10.1523/JNEUROSCI.21-19-07598.2001

PubMed Abstract | CrossRef Full Text | Google Scholar

Cahill, C. M., Xue, L., Grenier, P., Magnussen, C., Lecour, S., and Olmstead, M. C. (2013). Changes in morphine reward in a model of neuropathic pain. Behav. Pharmacol. 24, 207–213. doi: 10.1097/FBP.0B013E3283618AC8

PubMed Abstract | CrossRef Full Text | Google Scholar

Carlezon, W. A., and Krystal, A. D. (2016). Kappa-opioid antagonists for psychiatric disorders: from bench to clinical trials. Depress Anxiety 33, 895–906. doi: 10.1002/DA.22500

PubMed Abstract | CrossRef Full Text | Google Scholar

CDC WONDER (2018). CDC/NCHS, National Vital Statistics System, Mortality. Atlanta, GA: CDC.

Google Scholar

Célèrier, E., Rivat, C., Jun, Y., Laulin, J. P., Larcher, A., Reynier, P., et al. (2000). Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of ketamine. Anesthesiology 92, 465–472. doi: 10.1097/00000542-200002000-00029

PubMed Abstract | CrossRef Full Text | Google Scholar

Center for Behavioral Health Statistics and Quality (2019). SAMHSA, National Survey on Drug Use and Health. Key Substance Use and Mental Health Indicators in the United States: Results from the 2018 National Survey on Drug Use and Health. Rockville, MD: HHS Public.

Google Scholar

Chartoff, E. H., and Mavrikaki, M. (2015). Sex differences in kappa opioid receptor function and their potential impact on addiction. Front. Neurosci. 9:466. doi: 10.3389/fnins.2015.00466

PubMed Abstract | CrossRef Full Text | Google Scholar

Chefer, V. I., and Ba, C. M. (2013). Kappa opioid receptors on dopaminergic neurons are necessary for kappa-mediated place aversion. Neuropsychopharmacology 38, 2623–2631. doi: 10.1038/npp.2013.171

PubMed Abstract | CrossRef Full Text | Google Scholar

Chefer, V. I., and Shippenberg, T. S. (2009). Augmentation of morphine-induced sensitization but reduction in morphine tolerance and reward in delta-opioid receptor knockout mice. Neuropsychopharmacology 34, 887–898. doi: 10.1038/npp.2008.128

PubMed Abstract | CrossRef Full Text | Google Scholar

Chen, Y., Mestek, A., Liu, J., Hurley, J. A., and Yu, L. (1993). Molecular cloning and functional expression of a mu-opioid receptor from rat brain. Mol. Pharmacol. 44, 8–12.

Google Scholar

Chou, R., Turner, J. A., Devine, E. B., Hansen, R. N., Sullivan, S. D., Blazina, I., et al. (2015). The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a national institutes of health pathways to prevention workshop. Am. College Phys. 162, 276–286. doi: 10.7326/M14-2559

PubMed Abstract | CrossRef Full Text | Google Scholar

Chu, L. F., Angst, M. S., and Clark, D. (2008). Opioid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations. Clin. J. Pain 24, 479–496. doi: 10.1097/AJP.0b013e31816b2f43

PubMed Abstract | CrossRef Full Text | Google Scholar

Chu Sin Chung, P., and Kieffer, B. L. (2013). Delta opioid receptors in brain function and diseases. Pharmacol. Ther. 140, 112–120. doi: 10.1016/J.PHARMTHERA.2013.06.003

PubMed Abstract | CrossRef Full Text | Google Scholar

Chung, C. P., Dupont, W. D., Murray, K. T., Hall, K., Stein, C. M., and Ray, W. A. (2019). Comparative out-of-hospital mortality of long-acting opioids prescribed for non-cancer pain: a retrospective cohort study. Pharmacoepidemiol. Drug Saf. 28, 48–53. doi: 10.1002/pds.4619

PubMed Abstract | CrossRef Full Text | Google Scholar

Chung, S., Pohl, S., Zeng, J., Civelli, O., and Reinscheid, R. K. (2006). Endogenous orphanin FQ/nociceptin is involved in the development of morphine tolerance. J. Pharmacol. Exp. Ther. 318, 262–267. doi: 10.1124/jpet.106.103960

PubMed Abstract | CrossRef Full Text | Google Scholar

Ciccocioppo, R., Angeletti, S., Sanna, P. P., Weiss, F., and Massi, M. (2000). Effect of nociceptin/orphanin FQ on the rewarding properties of morphine. Eur. J. Pharmacol. 404, 153–159. doi: 10.1016/S0014-2999(00)00590-2

CrossRef Full Text | Google Scholar

Ciccocioppo, R., Economidou, D., Fedeli, A., Angeletti, S., Weiss, F., Heilig, M., et al. (2004). Attenuation of ethanol self-administration and of conditioned reinstatement of alcohol-seeking behaviour by the antiopioid peptide nociceptin/orphanin FQ in alcohol-preferring rats. Psychopharmacology 172, 170–178. doi: 10.1007/S00213-003-1645-1

PubMed Abstract | CrossRef Full Text | Google Scholar

Ciccocioppo, R., Panocka, I., Polidori, C., Regoli, D., and Massi, M. (1999). Effect of nociceptin on alcohol intake in alcohol-preferring rats. Psychopharmacology 141, 220–224. doi: 10.1007/S002130050828

PubMed Abstract | CrossRef Full Text | Google Scholar

Cicero, T. J., Ellis, M. S., and Chilcoat, H. D. (2018). Understanding the use of diverted buprenorphine. Drug Alcohol Depend. 193, 117–123. doi: 10.1016/J.DRUGALCDEP.2018.09.007

PubMed Abstract | CrossRef Full Text | Google Scholar

Clarke, T. K., Ambrose-Lanci, L., Ferraro, T. N., Berrettini, W. H., Kampman, K. M., Dackis, C. A., et al. (2012). Genetic association analyses of PDYN polymorphisms with heroin and cocaine addiction. Genes Brain Behav. 11, 415–423. doi: 10.1111/J.1601-183X.2012.00785.X

PubMed Abstract | CrossRef Full Text | Google Scholar

Colpaert, F. C., Meert, T., de Witte, P., and Schmitt, P. (1982). Further evidence validating adjuvant arthritis as an experimental model of chronic pain in the rat. Life Sci. 31, 67–75. doi: 10.1016/0024-3205(82)90402-7

CrossRef Full Text | Google Scholar

Colpaert, F. C., Tarayre, J. P., Alliaga, M., Bruins Slot, L. A., Attal, N., and Koek, W. (2001). Opiate self-administration as a measure of chronic nociceptive pain in arthritic rats. Pain 91, 33–45. doi: 10.1016/S0304-3959(00)00413-9

CrossRef Full Text | Google Scholar

Compton, W. M., and Volkow, N. D. (2006). Major increases in opioid analgesic abuse in the United States: concerns and strategies. Drug Alcohol Depend. 81, 103–107. doi: 10.1016/j.drugalcdep.2005.05.009

PubMed Abstract | CrossRef Full Text | Google Scholar

Cong, X., Maurel, D., Déméné, H., Vasiliauskaité-Brooks, I., Hagelberger, J., Peysson, F., et al. (2021). Molecular insights into the biased signaling mechanism of the μ-opioid receptor. Mol. Cell 81, 4165.e6–4175.e6. doi: 10.1016/j.molcel.2021.07.033

PubMed Abstract | CrossRef Full Text | Google Scholar

Contet, C., Kieffer, B. L., and Befort, K. (2004). Mu opioid receptor: a gateway to drug addiction. Curr. Opin. Neurobiol. 14, 370–378. doi: 10.1016/J.CONB.2004.05.005

PubMed Abstract | CrossRef Full Text | Google Scholar

Conway, S. M., Puttick, D., Russell, S., Potter, D., Roitman, M. F., and Chartoff, E. H. (2019). Females are less sensitive than males to the motivational- and dopamine-suppressing effects of kappa opioid receptor activation. Neuropharmacology 146, 231–241.

Google Scholar

Corder, G., Castro, D. C., Bruchas, M. R., and Scherrer, G. (2018). Endogenous and exogenous opioids in pain. Annu. Rev. Neurosci. 41, 453–473. doi: 10.1146/annurev-neuro-080317-061522

PubMed Abstract | CrossRef Full Text | Google Scholar

Corder, G., Tawfik, V. L., Wang, D., Sypek, E. I., Low, S. A., Dickinson, J. R., et al. (2017). Loss of μ opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia. Nat. Med. 23, 164–173. doi: 10.1038/nm.4262

PubMed Abstract | CrossRef Full Text | Google Scholar

Cork, R., Hameroff, S., and Weiss, J. (1985). Effects of halothane and fentanyl anesthesia on plasma β-endorphin immunoreactivity during cardiac surgery. Anesth. Analg. 64, 677–680.

PubMed Abstract | Google Scholar

Cowan, A., Lewis, J. W., and Macfarlane, I. R. (1977). Agonist and antagonist properties of buprenorphine, a new antinociceptive agent. Br. J. Pharmacol. 60, 537–545. doi: 10.1111/j.1476-5381.1977.tb07532.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Cox, B. M., Goldstein, A., and Li, C. H. (1976). Opioid activity of a peptide, beta-lipotropin-(61-91), derived from beta-lipotropin. Proc. Natl. Acad. Sci. U.S.A. 73, 1821–1823. doi: 10.1073/PNAS.73.6.1821

PubMed Abstract | CrossRef Full Text | Google Scholar

Crist, R. C., Ambrose-Lanci, L. M., Vaswani, M., Clarke, T. K., Zeng, A., Yuan, C., et al. (2013). Case-control association analysis of polymorphisms in the delta-opioid receptor, OPRD1, with cocaine and opioid addicted populations. Drug Alcohol Depend. 127, 122–128. doi: 10.1016/j.drugalcdep.2012.06.023

PubMed Abstract | CrossRef Full Text | Google Scholar

Cui, Y., Ostlund, S. B., James, A. S., Park, C. S., Ge, W., Roberts, K. W., et al. (2014). Targeted expression of μ-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward. Nat. Neurosci. 17, 254–261. doi: 10.1038/NN.3622

PubMed Abstract | CrossRef Full Text | Google Scholar

Cunha, A. M., Esteves, M., Pereira-Mendes, J., Guimarães, M. R., Almeida, A., and Leite-Almeida, H. (2020). High trait impulsivity potentiates the effects of chronic pain on impulsive behavior. Neurobiol. Pain 7:100042. doi: 10.1016/J.YNPAI.2019.100042

PubMed Abstract | CrossRef Full Text | Google Scholar

Dagnino, A. P. A., da Silva, R. B. M., Chagastelles, P. C., Pereira, T. C. B., Venturin, G. T., Greggio, S., et al. (2019). Nociceptin/orphanin FQ receptor modulates painful and fatigue symptoms in a mouse model of fibromyalgia. Pain 160, 1383–1401. doi: 10.1097/J.PAIN.0000000000001513

PubMed Abstract | CrossRef Full Text | Google Scholar

Dahan, A., van Dam, C. J., Niesters, M., van Velzen, M., Fossler, M. J., Demitrack, M. A., et al. (2020). Benefit and risk evaluation of biased μ-receptor agonist oliceridine versus morphine. Anesthesiology 133, 559–568. doi: 10.1097/ALN.0000000000003441

PubMed Abstract | CrossRef Full Text | Google Scholar

Darcq, E., and Kieffer, B. L. (2018). Opioid receptors: drivers to addiction? Nat. Rev. Neurosci. 19, 499–514. doi: 10.1038/s41583-018-0028-x

PubMed Abstract | CrossRef Full Text | Google Scholar

DaSilva, A. F., Nascimento, T. D., DosSantos, M. F., Lucas, S., van Holsbeeck, H., DeBoer, M., et al. (2014). μ-Opioid activation in the prefrontal cortex in migraine attacks – brief report I. Ann. Clin. Transl. Neurol. 1:439. doi: 10.1002/ACN3.65

PubMed Abstract | CrossRef Full Text | Google Scholar

David, V., Matifas, A., Gavello-Baudy, S., Decorte, L., Kieffer, B. L., and Cazala, P. (2008). Brain regional Fos expression elicited by the activation of mu- but not delta-opioid receptors of the ventral tegmental area: evidence for an implication of the ventral thalamus in opiate reward. Neuropsychopharmacology 33, 1746–1759. doi: 10.1038/SJ.NPP.1301529

PubMed Abstract | CrossRef Full Text | Google Scholar

Davis, A. M., and Inturrisi, C. E. (1999). d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia. J. Pharmacol. Exp. Ther. 289, 1048–1053.

PubMed Abstract | Google Scholar

Davis, M. A., Lin, L. A., Liu, H., and Sites, B. D. (2017). Prescription opioid use among adults with mental health disorders in the United States. J. Am. Board Fam. Med. 30, 407–417. doi: 10.3122/JABFM.2017.04.170112

PubMed Abstract | CrossRef Full Text | Google Scholar

DeLeo, J. A., Tanga, F. Y., and Tawfik, V. L. (2004). Neuroimmune activation and neuroinflammation in chronic pain and opioid tolerance/hyperalgesia. Neuroscientist 10, 40–52. doi: 10.1177/1073858403259950

PubMed Abstract | CrossRef Full Text | Google Scholar

Depner, U. B., Reinscheid, R. K., Takeshima, H., Brune, K., and Zeilhofer, H. U. (2003). Normal sensitivity to acute pain, but increased inflammatory hyperalgesia in mice lacking the nociceptin precursor polypeptide or the nociceptin receptor. Eur. J. Neurosci. 17, 2381–2387. doi: 10.1046/J.1460-9568.2003.02676.X

PubMed Abstract | CrossRef Full Text | Google Scholar

Derouiche, L., Pierre, F., Doridot, S., Ory, S., and Massotte, D. (2020). Heteromerization of endogenous mu and delta opioid receptors induces ligand-selective co-targeting to lysosomes. Molecules 25:4493. doi: 10.3390/molecules25194493

PubMed Abstract | CrossRef Full Text | Google Scholar

Devine, D. P., Reinscheid, R. K., Monsma, F. J., Civelli, O., and Akil, H. (1996). The novel neuropeptide orphanin FQ fails to produce conditioned place preference or aversion. Brain Res. 727, 225–229. doi: 10.1016/0006-8993(96)00476-3

CrossRef Full Text | Google Scholar

Devine, D. P., and Wise, R. A. (1994). Self-administration of morphine, DAMGO, and DPDPE into the ventral tegmental area of rats. J. Neurosci. 14, 1978–1984. doi: 10.1523/jneurosci.14-04-01978.1994

PubMed Abstract | CrossRef Full Text | Google Scholar

DeWire, S. M., Yamashita, D. S., Rominger, D. H., Liu, G., Cowan, C. L., Graczyk, T. M., et al. (2013). A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphines. J. Pharmacol. Exp. Ther. 344, 708–717. doi: 10.1124/jpet.112.201616

PubMed Abstract | CrossRef Full Text | Google Scholar

Dickenson, A. H., Navratilova, E., Patel, R., Porreca, F., and Bannister, K. (2020). Supraspinal opioid circuits differentially modulate spinal neuronal responses in neuropathic rats. Anesthesiology 132, 881–894. doi: 10.1097/ALN.0000000000003120

PubMed Abstract | CrossRef Full Text | Google Scholar

Dickenson, A. H., Sullivan, A. F., and McQuay, H. J. (1990). Intrathecal etorphine, fentanyl and buprenorphine on spinal nociceptive neurones in the rat. Pain 42, 227–234. doi: 10.1016/0304-3959(90)91166-G

CrossRef Full Text | Google Scholar

Dietis, N., Rowbotham, D. J., and Lambert, D. G. (2011). Opioid receptor subtypes: fact or artifact? Br. J. Anaesth. 107, 8–18. doi: 10.1093/BJA/AER115

PubMed Abstract | CrossRef Full Text | Google Scholar

Dole, V. P., and Nyswander, M. (1965). A medical treatment for diacetylmorphine (Heroin) addiction: a clinical trial with methadone hydrochloride. JAMA 193, 646–650. doi: 10.1001/JAMA.1965.03090080008002

PubMed Abstract | CrossRef Full Text | Google Scholar

Dole, V. P., and Nyswander, M. E. (1976). Methadone maintenance treatment: a ten-year perspective. JAMA 235, 2117–2119. doi: 10.1001/JAMA.1976.03260450029025

CrossRef Full Text | Google Scholar

Donica, C. L., Awwad, H. O., Thakker, D. R., and Standifer, K. M. (2013). Cellular mechanisms of nociceptin/orphanin FQ (N/OFQ) Peptide (NOP) receptor regulation and heterologous regulation by N/OFQ. Mol. Pharmacol. 83, 907–918. doi: 10.1124/MOL.112.084632

PubMed Abstract | CrossRef Full Text | Google Scholar

Donnelly, C. R., Andriessen, A. S., Chen, G., Wang, K., Jiang, C., Maixner, W., et al. (2020). Central nervous system targets: glial cell mechanisms in chronic pain. Neurotherapeutics 17, 846–860. doi: 10.1007/S13311-020-00905-7

PubMed Abstract | CrossRef Full Text | Google Scholar

DosSantos, M. F., Martikainen, I. K., Nascimento, T. D., Love, T. M., Deboer, M. D., Maslowski, E. C., et al. (2012). Reduced basal ganglia μ-opioid receptor availability in trigeminal neuropathic pain: a pilot study. Mol. Pain 8:74. doi: 10.1186/1744-8069-8-74

PubMed Abstract | CrossRef Full Text | Google Scholar

DosSantos, M. F., Moura, B., de, S., and DaSilva, A. F. (2017). Reward circuitry plasticity in pain perception and modulation. Front. Pharmacol. 8:790. doi: 10.3389/fphar.2017.00790

PubMed Abstract | CrossRef Full Text | Google Scholar

Doyle, M. A., and Mazei-Robison, M. S. (2021). Opioid-induced molecular and cellular plasticity of ventral tegmental area dopamine neurons. Cold Spring Harb. Perspect. Med. 11, 1–15. doi: 10.1101/cshperspect.a039362

PubMed Abstract | CrossRef Full Text | Google Scholar

Drdla, R., Gassner, M., Gingl, E., and Sandkühler, J. (2009). Induction of synaptic long-term potentiation after opioid withdrawal. Science 325, 207–210. doi: 10.1126/SCIENCE.1171759/SUPPL_FILE/DRDLA.SOM.PDF

CrossRef Full Text | Google Scholar

Drdla-Schutting, R., Benrath, J., Wunderbaldinger, G., and Sandkühler, J. (2012). Erasure of a spinal memory trace of pain by a brief, high-dose opioid administration. Science 335, 235–238. doi: 10.1126/SCIENCE.1211726/SUPPL_FILE/DRDLA-SCHUTTING.SOM.PDF

CrossRef Full Text | Google Scholar

Duarte, D. F. (2005). Opium and opioids: a brief history. Rev. Bras. Anestesiol. 55, 135–146. doi: 10.1590/S0034-70942005000100015

CrossRef Full Text | Google Scholar

Dubois, M., Pickar, D., Cohen, M., Gadde, P., Macnamara, T. E., and Bunney, W. E. (1982). Effects of fentanyl on the response of plasma beta-endorphin immunoreactivity to surgery. Anesthesiology 57, 468–472. doi: 10.1097/00000542-198212000-00006

PubMed Abstract | CrossRef Full Text | Google Scholar

Dumas, E. O., and Pollack, G. M. (2008). Opioid tolerance development: a pharmacokinetic/pharmacodynamic perspective. AAPS J. 10, 537–551. doi: 10.1208/s12248-008-9056-1

PubMed Abstract | CrossRef Full Text | Google Scholar

Economidou, D., Hansson, A. C., Weiss, F., Terasmaa, A., Sommer, W. H., Cippitelli, A., et al. (2008). Dysregulation of nociceptin/orphanin FQ activity in the amygdala is linked to excessive alcohol drinking in the rat. Biol. Psychiatry 64, 211–218. doi: 10.1016/j.biopsych.2008.02.004

PubMed Abstract | CrossRef Full Text | Google Scholar

Eidson, L. N., Inoue, K., Young, L. J., Tansey, M. G., and Murphy, A. Z. (2016). Toll-like receptor 4 mediates morphine-induced neuroinflammation and tolerance via soluble tumor necrosis factor signaling. Neuropsychopharmacology 42, 661–670. doi: 10.1038/npp.2016.131

PubMed Abstract | CrossRef Full Text | Google Scholar

Eidson, L. N., and Murphy, A. Z. (2019). Inflammatory mediators of opioid tolerance: implications for dependency and addiction. Peptides 115, 51–58. doi: 10.1016/j.peptides.2019.01.003

PubMed Abstract | CrossRef Full Text | Google Scholar

Eikemo, M., Løseth, G. E., and Leknes, S. (2021). Do endogenous opioids mediate or fine-tune human pain relief? Pain 162, 2789–2791. doi: 10.1097/j.pain.0000000000002286

PubMed Abstract | CrossRef Full Text | Google Scholar

Elman, I., and Borsook, D. (2016). Common brain mechanisms of chronic pain and addiction. Neuron 89, 11–36. doi: 10.1016/j.neuron.2015.11.027

PubMed Abstract | CrossRef Full Text | Google Scholar

Emery, M. A., and Akil, H. (2020). Endogenous opioids at the intersection of opioid addiction, pain, and depression: the search for a precision medicine approach. Annu. Rev. Neurosci. 43, 355–374. doi: 10.1146/annurev-neuro-110719-095912

PubMed Abstract | CrossRef Full Text | Google Scholar

Escobar, A., del, P., Casanova, J. P., Andrés, M. E., and Fuentealba, J. A. (2020). Crosstalk between kappa opioid and dopamine systems in compulsive behaviors. Front. Pharmacol. 11:57. doi: 10.3389/FPHAR.2020.00057/BIBTEX

CrossRef Full Text | Google Scholar

Evans, C. J., Keith, D. E., Morrison, H., Magendzo, K., and Edwards, R. H. (1992). Cloning of a delta opioid receptor by functional expression. Science 258, 1952–1955. doi: 10.1126/science.1335167

PubMed Abstract | CrossRef Full Text | Google Scholar

Ewan, E. E., and Martin, T. J. (2011). Opioid facilitation of rewarding electrical brain stimulation is suppressed in rats with neuropathic pain. Anesthesiology 114, 624–632. doi: 10.1097/ALN.0b013e31820a4edb

PubMed Abstract | CrossRef Full Text | Google Scholar

Fallon, N., Brown, C., Twiddy, H., Brian, E., Frank, B., Nurmikko, T., et al. (2021). Adverse effects of COVID-19-related lockdown on pain, physical activity and psychological well-being in people with chronic pain. Br. J. Pain 15, 357–368. doi: 10.1177/2049463720973703

PubMed Abstract | CrossRef Full Text | Google Scholar

Ferrari, A., Coccia, C. P. R., Bertolini, A., and Sternieri, E. (2004). Methadone—metabolism, pharmacokinetics and interactions. Pharmacol. Res. 50, 551–559. doi: 10.1016/J.PHRS.2004.05.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Fibiger, H. C., LePiane, F. G., Jakubovic, A., and Phillips, A. G. (1987). The role of dopamine in intracranial self-stimulation of the ventral tegmental area. J. Neurosci. 7, 3888–3896. doi: 10.1523/jneurosci.07-12-03888.1987

PubMed Abstract | CrossRef Full Text | Google Scholar

Filliol, D., Ghozland, S., Chluba, J., Martin, M., Matthes, H. W. D., Simonin, F., et al. (2000). Mice deficient for δ- and μ-opioid receptors exhibit opposing alterations of emotional responses. Nat. Genet. 25, 195–200. doi: 10.1038/76061

PubMed Abstract | CrossRef Full Text | Google Scholar

Florence, C., Luo, F., and Rice, K. (2021). The economic burden of opioid use disorder and fatal opioid overdose in the United States, 2017. Drug Alcohol Depend. 218:108350. doi: 10.1016/j.drugalcdep.2020.108350

PubMed Abstract | CrossRef Full Text | Google Scholar

Florin, S., Meunier, J. C., and Costentin, J. (2000). Autoradiographic localization of [3H]nociceptin binding sites in the rat brain. Brain Res. 880, 11–16. doi: 10.1016/S0006-8993(00)02669-X

CrossRef Full Text | Google Scholar

Frank, S., Veit, R., Sauer, H., Enck, P., Friederich, H. C., Unholzer, T., et al. (2016). Dopamine depletion reduces food-related reward activity independent of BMI. Neuropsychopharmacology 41, 1551–1559. doi: 10.1038/npp.2015.313

PubMed Abstract | CrossRef Full Text | Google Scholar

Friedrich, A. E., and Gebhart, G. F. (2003). Modulation of visceral hyperalgesia by morphine and cholecystokinin from the rat rostroventral medial medulla. Pain 104, 93–101. doi: 10.1016/S0304-3959(02)00469-4

CrossRef Full Text | Google Scholar

Galaj, E., Han, X., Shen, H., Jordan, C. J., He, Y., Humburg, B., et al. (2020). Dissecting the role of GABA neurons in the VTA versus SNr in opioid reward. J. Neurosci. 40, 8853–8869. doi: 10.1523/JNEUROSCI.0988-20.2020

PubMed Abstract | CrossRef Full Text | Google Scholar

Gaskin, D. J., and Richard, P. (2012). The economic costs of pain in the United States. J. Pain 13, 715–724. doi: 10.1016/J.JPAIN.2012.03.009

PubMed Abstract | CrossRef Full Text | Google Scholar

Gavériaux-Ruff, C., Karchewski, L. A., Hever, X., Matifas, A., and Kieffer, B. L. (2008). Inflammatory pain is enhanced in delta opioid receptor-knockout mice. Eur. J. Neurosci. 27, 2558–2567. doi: 10.1111/J.1460-9568.2008.06223.X

PubMed Abstract | CrossRef Full Text | Google Scholar

Gaveriaux-Ruff, C., Nozaki, C., Nadal, X., Hever, X. C., Weibel, R., Matifas, A., et al. (2011). Genetic ablation of delta opioid receptors in nociceptive sensory neurons increases chronic pain and abolishes opioid analgesia. Pain 152, 1238–1248. doi: 10.1016/J.PAIN.2010.12.031

PubMed Abstract | CrossRef Full Text | Google Scholar

Gendron, L., Esdaile, M. J., Mennicken, F., Pan, H., O’Donnell, D., Vincent, J. P., et al. (2007a). Morphine priming in rats with chronic inflammation reveals a dichotomy between antihyperalgesic and antinociceptive properties of deltorphin. Neuroscience 144, 263–274. doi: 10.1016/J.NEUROSCIENCE.2006.08.077

PubMed Abstract | CrossRef Full Text | Google Scholar

Gendron, L., Pintar, J. E., and Chavkin, C. (2007b). Essential role of mu opioid receptor in the regulation of delta opioid receptor-mediated antihyperalgesia. Neuroscience 150, 807–817. doi: 10.1016/J.NEUROSCIENCE.2007.09.060

PubMed Abstract | CrossRef Full Text | Google Scholar

Gendron, L., Lucido, A. L., Mennicken, F., O’Donnell, D., Vincent, J. P., Stroh, T., et al. (2006). Morphine and pain-related stimuli enhance cell surface availability of somatic δ-opioid receptors in rat dorsal root ganglia. J. Neurosci. 26, 953–962. doi: 10.1523/JNEUROSCI.3598-05.2006

PubMed Abstract | CrossRef Full Text | Google Scholar

Ghozland, S., Matthes, H. W. D., Simonin, F., Filliol, D., Kieffer, B. L., and Maldonado, R. (2002). Motivational effects of cannabinoids are mediated by μ-opioid and κ-opioid receptors. J. Neurosci. 22, 1146–1154. doi: 10.1523/jneurosci.22-03-01146.2002

PubMed Abstract | CrossRef Full Text | Google Scholar

Goldstick, J. E., Guy, G. P., Losby, J. L., Baldwin, G., Myers, M., and Bohnert, A. S. B. (2021). Changes in initial opioid prescribing practices after the 2016 release of the CDC guideline for prescribing opioids for chronic pain. JAMA Netw. Open 4:e2116860. doi: 10.1001/JAMANETWORKOPEN.2021.16860

PubMed Abstract | CrossRef Full Text | Google Scholar

Gomes, I., Gupta, A., Filipovska, J., Szeto, H. H., Pintar, J. E., and Devi, L. A. (2004). A role for heterodimerization of mu and delta opiate receptors in enhancing morphine analgesia. Proc. Natl. Acad. Sci. U.S.A. 101, 5135–5139. doi: 10.1073/PNAS.0307601101

PubMed Abstract | CrossRef Full Text | Google Scholar

Graeme Henderson, C., Hill, R., Disney, A., Conibear, A., Sutcliffe, K., Dewey, W., et al. (2018). The novel μ-opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception. Br. J. Pharmacol. 175:2653. doi: 10.1111/bph.14224

PubMed Abstract | CrossRef Full Text | Google Scholar

Grol-Prokopczyk, H. (2017). Sociodemographic disparities in chronic pain, based on 12-year longitudinal data. Pain 158, 313–322. doi: 10.1097/J.PAIN.0000000000000762

PubMed Abstract | CrossRef Full Text | Google Scholar

Gudin, J., and Fudin, J. (2020). A narrative pharmacological review of buprenorphine: a unique opioid for the treatment of chronic pain. Pain Ther. 9, 41–54. doi: 10.1007/S40122-019-00143-6/TABLES/2

CrossRef Full Text | Google Scholar

Hagelberg, N., Aalto, S., Tuominen, L., Pesonen, U., Någren, K., Hietala, J., et al. (2012). Striatal μ-opioid receptor availability predicts cold pressor pain threshold in healthy human subjects. Neurosci. Lett. 521, 11–14. doi: 10.1016/J.NEULET.2012.05.042

PubMed Abstract | CrossRef Full Text | Google Scholar

Halbert, B. T., Davis, R. B., and Wee, C. C. (2016). Disproportionate longer-term opioid use among US adults with mood disorders. Pain 157:2452. doi: 10.1097/J.PAIN.0000000000000650

PubMed Abstract | CrossRef Full Text | Google Scholar

Hans, B., Kosterlitz, H., and Hughes, J. (1977). Peptides with morphine-like action in the brain. Br. J. Psychiatry 130, 298–304. doi: 10.1192/BJP.130.3.298

PubMed Abstract | CrossRef Full Text | Google Scholar

Hao, J. X., Xu, I. S., Wiesenfeld-Hallin, Z., and Xu, X. J. (1998). Anti-hyperalgesic and anti-allodynic effects of intrathecal nociceptin/orphanin FQ in rats after spinal cord injury, peripheral nerve injury and inflammation. Pain 76, 385–393. doi: 10.1016/S0304-3959(98)00071-2

CrossRef Full Text | Google Scholar

Hargreaves, K. M., Dionne, R. A., Mueller, G. P., Goldstein, D. S., and Dubner, R. (1986). Naloxone, fentanyl, and diazepam modify plasma beta-endorphin levels during surgery. Clin. Pharmacol. Ther. 40, 165–171. doi: 10.1038/CLPT.1986.159

PubMed Abstract | CrossRef Full Text | Google Scholar

Harris, R. E., Clauw, D. J., Scott, D. J., Mclean, S. A., Gracely, R. H., and Zubieta, J.-K. (2007). Neurobiology of disease decreased central-opioid receptor availability in fibromyalgia. J. Neurosci. 27, 10000–10006. doi: 10.1523/JNEUROSCI.2849-07.2007

PubMed Abstract | CrossRef Full Text | Google Scholar

Hassan, A. H. S., Ableitner, A., Stein, C., and Herz, A. (1993). Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in the inflamed tissue. Neuroscience 55, 185–195. doi: 10.1016/0306-4522(93)90465-R

CrossRef Full Text | Google Scholar

Hay, J. L., White, J. M., Bochner, F., Somogyi, A. A., Semple, T. J., and Rounsefell, B. (2009). Hyperalgesia in opioid-managed chronic pain and opioid-dependent patients. J. Pain 10, 316–322. doi: 10.1016/J.JPAIN.2008.10.003

PubMed Abstract | CrossRef Full Text | Google Scholar

Hayes, A. G., and Stewart, B. R. (1985). Effect of μ and κ opioid receptor agonists on rat plasma corticosterone levels. Eur. J. Pharmacol. 116, 75–79. doi: 10.1016/0014-2999(85)90186-4

CrossRef Full Text | Google Scholar

Hayes, C., Krebs, E., Hudson, T., Brown, J., Li, C., and Martin, B. (2019). PMS31 impact of opioid dose escalation on the development of substance use disorders, accidents, self-inflicted injuries, opioid overdoses, and alcohol and non-opioid drug-related overdoses: a retrospective cohort study. Value Health 22:S244. doi: 10.1016/j.jval.2019.04.1141

CrossRef Full Text | Google Scholar

Hayes, C. J., Krebs, E. E., Hudson, T., Brown, J., Li, C., and Martin, B. C. (2020). Impact of opioid dose escalation on pain intensity. Pain 161, 979–988. doi: 10.1097/j.pain.0000000000001784

PubMed Abstract | CrossRef Full Text | Google Scholar

Hayhurst, C. J., and Durieux, M. E. (2016). Differential opioid tolerance and opioid-induced hyperalgesiaa clinical reality. Anesthesiology 124, 483–488. doi: 10.1097/ALN.0000000000000963

PubMed Abstract | CrossRef Full Text | Google Scholar

Heinl, C., Drdla-Schutting, R., Xanthos, D. N., and Sandkühler, J. (2011). Distinct mechanisms underlying pronociceptive effects of opioids. J. Neurosci. 31, 16748–16756. doi: 10.1523/JNEUROSCI.3491-11.2011

PubMed Abstract | CrossRef Full Text | Google Scholar

Heinricher, M. M., and Neubert, M. J. (2004). Neural basis for the hyperalgesic action of cholecystokinin in the rostral ventromedial medulla. J. Neurophysiol. 92, 1982–1989. doi: 10.1152/JN.00411.2004/ASSET/IMAGES/LARGE/Z9K0100441300007.JPEG

CrossRef Full Text | Google Scholar

Hertz, S. (2018). FDA Briefing Document Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) Meeting. Silver Spring, MD: Food and Drug Administration, 1–115.

Google Scholar

Higgins, C., Smith, B. H., and Matthews, K. (2020). Comparison of psychiatric comorbidity in treatment-seeking, opioid-dependent patients with versus without chronic pain. Addiction 115, 249–258. doi: 10.1111/ADD.14768

PubMed Abstract | CrossRef Full Text | Google Scholar

Hipólito, L., Sánchez-Catalán, M. J., Zanolini, I., Polache, A., and Granero, L. (2008). Shell/core differences in mu- and delta-opioid receptor modulation of dopamine efflux in nucleus accumbens. Neuropharmacology 55, 183–189. doi: 10.1016/J.NEUROPHARM.2008.05.012

PubMed Abstract | CrossRef Full Text | Google Scholar

Hipólito, L., Wilson-Poe, A., Campos-Jurado, Y., Zhong, E., Gonzalez-Romero, J., Virag, L., et al. (2015). Inflammatory pain promotes increased opioid self-administration: role of dysregulated ventral tegmental area μ opioid receptors. J. Neurosci. 35, 12217–12231. doi: 10.1523/JNEUROSCI.1053-15.2015

PubMed Abstract | CrossRef Full Text | Google Scholar

Hirose, N., Murakawa, K., Takada, K., Oi, Y., Suzuki, T., Nagase, H., et al. (2005). Interactions among mu- and delta-opioid receptors, especially putative delta1- and delta2-opioid receptors, promote dopamine release in the nucleus accumbens. Neuroscience 135, 213–225. doi: 10.1016/J.NEUROSCIENCE.2005.03.065

PubMed Abstract | CrossRef Full Text | Google Scholar

Højsted, J., and Sjøgren, P. (2007). Addiction to opioids in chronic pain patients: a literature review. Eur. J. Pain 11, 490–518. doi: 10.1016/J.EJPAIN.2006.08.004

PubMed Abstract | CrossRef Full Text | Google Scholar

Horikawa, S., Takai, T., Toyosato, M., Takahashi, H., Noda, M., Kakidani, H., et al. (1983). Isolation and structural organization of the human preproenkephalin Bgene. Nature 306, 611–614. doi: 10.1038/306611a0

PubMed Abstract | CrossRef Full Text | Google Scholar

Hser, Y. I., Mooney, L. J., Saxon, A. J., Miotto, K., Bell, D. S., and Huang, D. (2017). Chronic pain among patients with opioid use disorder: results from electronic health records data. J. Subst. Abuse Treat. 77, 26–30. doi: 10.1016/J.JSAT.2017.03.006

PubMed Abstract | CrossRef Full Text | Google Scholar

Hughes, J., Kosterlitz, H. W., and Smith, T. W. (1977). The distribution of methionin-enkephalin in the brain and peripheral tissues. Br. J. Pharmacol. 61, 639–647. doi: 10.1111/j.1476-5381.1977.tb07557.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Huhn, A. S., Berry, M. S., and Dunn, K. E. (2018). Systematic review of sex-based differences in opioid-based effects. Int. Rev. Psychiatry 30, 107–116. doi: 10.1080/09540261.2018.1514295

PubMed Abstract | CrossRef Full Text | Google Scholar

Hurd, Y. L., Herman, M. M., Hyde, T. M., Bigelow, L. B., Weinberger, D. R., and Kleinman, J. E. (1997). Prodynorphin mRNA expression is increased in the patch vs matrix compartment of the caudate nucleus in suicide subjects. Mol. Psychiatry 2, 495–500. doi: 10.1038/SJ.MP.4000319

PubMed Abstract | CrossRef Full Text | Google Scholar

Hutchings, J. B., Crampton, D., Morris, S. L., Durand, D., Steinbring, E., Combes, F., et al. (1997). References and Notes Enhanced Morphine Analgesia in Mice Lacking-Arrestin 2. Available online at: https://www.science.org (accessed April 24, 2022).

Google Scholar

Iadarola, M. J., Brady, L. S., Draisci, G., and Dubner, R. (1988). Enhancement of dynorphin gene expression in spinal cord following experimental inflammation: stimulus specificity, behavioral parameters and opioid receptor binding. Pain 35, 313–326. doi: 10.1016/0304-3959(88)90141-8

CrossRef Full Text | Google Scholar

Ikeda, K., Kobayashi, T., Kumanishi, T., Niki, H., and Yano, R. (2000). Involvement of G-protein-activated inwardly rectifying K+ (GIRK) channels in opioid-induced analgesia. Neurosci. Res. 38, 113–116. doi: 10.1016/S0168-0102(00)00144-9

CrossRef Full Text | Google Scholar

Institute of Medicine Committee on Advancing Pain Research (2011). Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: National Academies Press.

Google Scholar

Iyengar, S., Kim, H. S., and Wood, P. L. (1986). Kappa opiate agonists modulate the hypothalamic-pituitary-adrenocortical axis in the rat. J. Pharmacol. Exp. Ther. 238, 429–436.

Google Scholar

Jantarada, C., Silva, C., and Guimarães-Pereira, L. (2021). Prevalence of problematic use of opioids in patients with chronic noncancer pain: a systematic review with meta-analysis. Pain Pract. 21, 715–729. doi: 10.1111/PAPR.13001

PubMed Abstract | CrossRef Full Text | Google Scholar

Jarcho, J. M., Mayer, E. A., Jiang, Z. K., Feier, N. A., and London, E. D. (2012). Pain, affective symptoms and cognitive deficits in patients with cerebral dopamine dysfunction. Pain 153, 744–754. doi: 10.1016/J.PAIN.2012.01.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Jassar, H., Nascimento, T. D., Kaciroti, N., Dossantos, M. F., Danciu, T., Koeppe, R. A., et al. (2019). Impact of chronic migraine attacks and their severity on the endogenous μ-opioid neurotransmission in the limbic system. Neuroimage Clin. 23:101905. doi: 10.1016/j.nicl.2019.101905

PubMed Abstract | CrossRef Full Text | Google Scholar

Ji, M. J., Yang, J., Gao, Z. Q., Zhang, L., and Liu, C. (2021). The role of the kappa opioid system in comorbid pain and psychiatric disorders: function and implications. Front. Neurosci. 15:130. doi: 10.3389/FNINS.2021.642493/BIBTEX

CrossRef Full Text | Google Scholar

Jones, C. M., and McCance-Katz, E. F. (2019). Co-occurring substance use and mental disorders among adults with opioid use disorder. Drug Alcohol Depend. 197, 78–82. doi: 10.1016/j.drugalcdep.2018.12.030

PubMed Abstract | CrossRef Full Text | Google Scholar

Jutkiewicz, E. M., Torregrossa, M. M., Sobczyk-Kojiro, K., Mosberg, H. I., Folk, J. E., Rice, K. C., et al. (2006). Behavioral and neurobiological effects of the enkephalinase inhibitor RB101 relative to its antidepressant effects. Eur. J. Pharmacol. 531, 151–159. doi: 10.1016/j.ejphar.2005.12.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Kabli, N., and Cahill, C. M. (2007). Anti-allodynic effects of peripheral delta opioid receptors in neuropathic pain. Pain 127, 84–93. doi: 10.1016/J.PAIN.2006.08.003

PubMed Abstract | CrossRef Full Text | Google Scholar

Kallupi, M., G Carrette, L. L., Kononoff, J., Solberg Woods, L. C., Palmer, A. A., Schweitzer, P., et al. (2020). Nociceptin attenuates the escalation of oxycodone self-administration by normalizing CeA–GABA transmission in highly addicted rats. Natl. Acad. Sci. 117, 2140–2148. doi: 10.1073/pnas.1915143117/-/DCSupplemental

PubMed Abstract | CrossRef Full Text | Google Scholar

Kaplan, H., and Fields, H. L. (1991). Hyperalgesia during acute opioid abstinence: evidence for a nociceptive facilitating function of the rostral ventromedial medulla. J. Neurosci. 11, 1433–1439. doi: 10.1523/jneurosci.11-05-01433.1991

PubMed Abstract | CrossRef Full Text | Google Scholar

Kaplovitch, E., Gomes, T., Camacho, X., Dhalla, I. A., Mamdani, M. M., and Juurlink, D. N. (2015). Sex differences in dose escalation and overdose death during chronic opioid therapy: a population-based cohort study. PLoS One 10:e0134550. doi: 10.1371/journal.pone.0134550

PubMed Abstract | CrossRef Full Text | Google Scholar

Karp, J. F., Butters, M. A., Begley, A. E., Miller, M. D., Lenze, E. J., Blumberger, D. M., et al. (2014). Safety, tolerability, and clinical effect of low-dose buprenorphine for treatment-resistant depression in midlife and older adults. J. Clin. Psychiatry 75, e785–e793. doi: 10.4088/JCP.13M08725

PubMed Abstract | CrossRef Full Text | Google Scholar

Kathmann, M., Flau, K., Redmer, A., Tränkle, C., and Schlicker, E. (2006). Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn. Schmiedebergs Arch. Pharmacol. 372, 354–361. doi: 10.1007/S00210-006-0033-X

PubMed Abstract | CrossRef Full Text | Google Scholar

Kendler, K. S., Jacobson, K. C., Prescott, C. A., and Neale, M. C. (2003). Specificity of genetic and environmental risk factors for use and abuse/dependence of cannabis, cocaine, hallucinogens, sedatives, stimulants, and opiates in male twins. Am. J. Psychiatry 160, 687–695. doi: 10.1176/APPI.AJP.160.4.687

PubMed Abstract | CrossRef Full Text | Google Scholar

Kieffer, B., Befort, K., Gaveriaux-Ruff, C., and Hirth, C. (1992). The delta-opioid receptor: isolation of a cDNA by expression cloning and pharmacological characterization. Proc. Natl. Acad. Sci. U.S.A. 89, 12048–12052. doi: 10.1073/PNAS.89.24.12048

PubMed Abstract | CrossRef Full Text | Google Scholar

Kliewer, A., Gillis, A., Hill, R., Schmiedel, F., Bailey, C., Kelly, E., et al. (2020). Morphine-induced respiratory depression is independent of β-arrestin2 signalling. Br. J. Pharmacol. 177, 2923–2931. doi: 10.1111/BPH.15004

PubMed Abstract | CrossRef Full Text | Google Scholar

Kliewer, A., Schmiedel, F., Sianati, S., Bailey, A., Bateman, J. T., Levitt, E. S., et al. (2019). Phosphorylation-deficient G-protein-biased μ-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effects. Nat. Commun. 10, 1–11. doi: 10.1038/s41467-018-08162-1

PubMed Abstract | CrossRef Full Text | Google Scholar

Ko, M. C., and Naughton, N. N. (2009). Antinociceptive effects of nociceptin/orphanin FQ administered intrathecally in monkeys. J. Pain 10, 509–516. doi: 10.1016/j.jpain.2008.11.006

PubMed Abstract | CrossRef Full Text | Google Scholar

Koch, T., and Höllt, V. (2008). Role of receptor internalization in opioid tolerance and dependence. Pharmacol. Ther. 117, 199–206. doi: 10.1016/J.PHARMTHERA.2007.10.003

PubMed Abstract | CrossRef Full Text | Google Scholar

Koob, G. F. (2020). Neurobiology of opioid addiction: opponent process, hyperkatifeia, and negative reinforcement. Biol. Psychiatry 87, 44–53. doi: 10.1016/j.biopsych.2019.05.023

PubMed Abstract | CrossRef Full Text | Google Scholar

Koob, G. F., and Volkow, N. D. (2010). Neurocircuitry of addiction. Neuropsychopharmacology 35, 217–238. doi: 10.1038/npp.2010.4

CrossRef Full Text | Google Scholar

Koppert, W., Ihmsen, H., Körber, N., Wehrfritz, A., Sittl, R., Schmelz, M., et al. (2005). Different profiles of buprenorphine-induced analgesia and antihyperalgesia in a human pain model. Pain 118, 15–22. doi: 10.1016/J.PAIN.2005.06.030

PubMed Abstract | CrossRef Full Text | Google Scholar

Kotlinska, J., Rafalski, P., Biala, G., Dylag, T., Rolka, K., and Silberring, J. (2003). Nociceptin inhibits acquisition of amphetamine-induced place preference and sensitization to stereotypy in rats. Eur. J. Pharmacol. 474, 233–239. doi: 10.1016/S0014-2999(03)02081-8

CrossRef Full Text | Google Scholar

Kotliñska, J., Wichmann, J., Legowska, A., Rolka, K., and Silberring, J. (2002). Orphanin FQ/nociceptin but not Ro 65-6570 inhibits the expression of cocaine-induced conditioned place preference. Behav. Pharmacol. 13, 229–235. doi: 10.1097/00008877-200205000-00006

PubMed Abstract | CrossRef Full Text | Google Scholar

Kovelowski, C. J., Ossipov, M. H., Sun, H., Lai, J., Malan, T. P., and Porreca, F. (2000). Supraspinal cholecystokinin may drive tonic descending facilitation mechanisms to maintain neuropathic pain in the rat. Pain 87, 265–273. doi: 10.1016/s0304-3959(00)00290-6

CrossRef Full Text | Google Scholar

Kreek, M. J. (1973). Medical safety and side effects of methadone in tolerant individuals. JAMA 223, 665–668. doi: 10.1001/jama.1973.03220060039009

CrossRef Full Text | Google Scholar

Kreek, M. J. (1991). Using Methadone Effectively: Achieving Goals by Application of Laboratory, Clinical, and Evaluation Research and by Development of Innovative Programs. Bethesda, MD: NIDA Research Monograph Series, 245–266.

Google Scholar

Kreek, M. J. (2000). Methadone-related opioid agonist pharmacotherapy for heroin addiction. History, recent molecular and neurochemical research and future in mainstream medicine. Ann. N.Y. Acad. Sci. 909, 186–216. doi: 10.1111/j.1749-6632.2000.tb06683.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Kreek, M. J., Borg, L., Ducat, E., and Ray, B. (2010). Pharmacotherapy in the treatment of addiction: methadone. J. Addict. Dis. 29, 200–216. doi: 10.1080/10550881003684798

PubMed Abstract | CrossRef Full Text | Google Scholar

Krishnamurti, C., and Rao, S. C. (2016). The isolation of morphine by Serturner. Indian J. Anaesth. 60:861. doi: 10.4103/0019-5049.193696

PubMed Abstract | CrossRef Full Text | Google Scholar

Kuzmin, A., Sandin, J., Terenius, L., and Ögren, S. O. (2004). Evidence in locomotion test for the functional heterogeneity of ORL-1 receptors. Br. J. Pharmacol. 141, 132–140. doi: 10.1038/sj.bjp.0705583

PubMed Abstract | CrossRef Full Text | Google Scholar

Lane, D. A., Tortorici, V., and Morgan, M. M. (2004). Behavioral and electrophysiological evidence for tolerance to continuous morphine administration into the ventrolateral periaqueductal gray. Neuroscience 125, 63–69. doi: 10.1016/J.NEUROSCIENCE.2004.01.023

PubMed Abstract | CrossRef Full Text | Google Scholar

Lappin, R. (2016). CDC issues new opioid prescribing guideline. Emerg. Med. 48, 150–151. doi: 10.15585/mmwr.rr6501e1er

CrossRef Full Text | Google Scholar

Latif, Z. E. H., Skjærvø, I., Solli, K. K., and Tanum, L. (2021). Chronic pain among patients with an opioid use disorder. Am. J. Addict. 30, 366–375. doi: 10.1111/ajad.13153

PubMed Abstract | CrossRef Full Text | Google Scholar

Laurent, V., Bertran-Gonzalez, J., Chieng, B. C., and Balleine, B. W. (2014). δ-Opioid and dopaminergic processes in accumbens shell modulate the cholinergic control of predictive learning and choice. J. Neurosci. 34, 1358–1369. doi: 10.1523/JNEUROSCI.4592-13.2014

PubMed Abstract | CrossRef Full Text | Google Scholar

Laurent, V., Leung, B., Maidment, N., and Balleine, B. W. (2012). μ- and δ-opioid-related processes in the accumbens core and shell differentially mediate the influence of reward-guided and stimulus-guided decisions on choice. J. Neurosci. 32, 1875–1883. doi: 10.1523/JNEUROSCI.4688-11.2012

PubMed Abstract | CrossRef Full Text | Google Scholar

le Merrer, J., Becker, J. A. J., Befort, K., and Kieffer, B. L. (2009). Reward processing by the opioid system in the brain. Physiol. Rev. 89, 1379–1412. doi: 10.1152/physrev.00005.2009

PubMed Abstract | CrossRef Full Text | Google Scholar

le Merrer, J., Plaza-Zabala, A., del Boca, C., Matifas, A., Maldonado, R., and Kieffer, B. L. (2011). Deletion of the δ opioid receptor gene impairs place conditioning but preserves morphine reinforcement. Biol. Psychiatry 69, 700–703. doi: 10.1016/J.BIOPSYCH.2010.10.021

PubMed Abstract | CrossRef Full Text | Google Scholar

Lee, M. C., and Tracey, I. (2010). Unravelling the mystery of pain, suffering, and relief with brain imaging. Curr. Pain Headache Rep. 14, 124–131. doi: 10.1007/S11916-010-0103-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Lee, M. O., Lee, M. O., Silverman, S., Hansen, H., Patel, V., and Manchikanti, L. (2011). A comprehensive review of opioid-induced hyperalgesia. Pain Phys. 14, 145–161.

Google Scholar

Leknes, S., Lee, M., Berna, C., Andersson, J., and Tracey, I. (2011). Relief as a reward: hedonic and neural responses to safety from pain. PLoS One 6:e17870. doi: 10.1371/JOURNAL.PONE.0017870

PubMed Abstract | CrossRef Full Text | Google Scholar

Leknes, S., and Tracey, I. (2008). A common neurobiology for pain and pleasure. Nat. Rev. Neurosci. 9, 314–320. doi: 10.1038/NRN2333

PubMed Abstract | CrossRef Full Text | Google Scholar

Liang, L., Lutz, B. M., Bekker, A., and Tao, Y. X. (2015). Epigenetic regulation of chronic pain. Epigenomics 7, 235–242. doi: 10.2217/EPI.14.75

PubMed Abstract | CrossRef Full Text | Google Scholar

Liang, Y., Chu, H., Jiang, Y., and Yuan, L. (2016). Morphine enhances IL-1β release through toll-like receptor 4-mediated endocytic pathway in microglia. Purinergic Signal 12, 637–645. doi: 10.1007/S11302-016-9525-4/FIGURES/7

CrossRef Full Text | Google Scholar

Ling, G. S. F., Paul, D., Simantov, R., and Pasternak, G. W. (1989). Differential development of acute tolerance to analgesia, respiratory depression, gastrointestinal transit and hormone release in a morphine infusion model. Life Sci. 45, 1627–1636. doi: 10.1016/0024-3205(89)90272-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Linz, K., Christoph, T., Tzschentke, T. M., Koch, T., Schiene, K., Gautrois, M., et al. (2014). Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. J. Pharmacol. Exp. Ther. 349, 535–548. doi: 10.1124/JPET.114.213694

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, S., Pickens, S., Burma, N. E., Ibarra-Lecue, I., Yang, H., Xue, L., et al. (2019). Neurobiology of disease kappa opioid receptors drive a tonic aversive component of chronic pain. J. Neurosci. 39, 4162–4178. doi: 10.1523/JNEUROSCI.0274-19.2019

PubMed Abstract | CrossRef Full Text | Google Scholar

Livingston, K. E., and Traynor, J. R. (2018). Allostery at opioid receptors: modulation with small molecule ligands. Br. J. Pharmacol. 175:2846. doi: 10.1111/BPH.13823

PubMed Abstract | CrossRef Full Text | Google Scholar

Llorca-Torralba, M., Pilar-Cuéllar, F., Bravo, L., Bruzos-Cidon, C., Torrecilla, M., Mico, J. A., et al. (2019a). Opioid activity in the locus coeruleus is modulated by chronic neuropathic pain. Mol. Neurobiol. 56, 4135–4150. doi: 10.1007/s12035-018-1361-9

PubMed Abstract | CrossRef Full Text | Google Scholar

Llorca-Torralba, M., Suárez-Pereira, I., Bravo, L., Camarena-Delgado, C., Garcia-Partida, J. A., Mico, J. A., et al. (2019b). Chemogenetic silencing of the locus coeruleus–basolateral amygdala pathway abolishes pain-induced anxiety and enhanced aversive learning in rats. Biol. Psychiatry 85, 1021–1035. doi: 10.1016/j.biopsych.2019.02.018

PubMed Abstract | CrossRef Full Text | Google Scholar

Lord, J. A. H., Waterfield, A. A., Hughes, J., and Kosterlitz, H. W. (1977). Endogenous opioid peptides: multiple agonists and receptors. Nature 267, 495–499.

Google Scholar

Loyd, D. R., Morgan, M. M., and Murphy, A. Z. (2008). Sexually dimorphic activation of the periaqueductal gray-rostral ventromedial medullary circuit during the development of tolerance to morphine in the rat. Eur. J. Neurosci. 27, 1517–1524. doi: 10.1111/J.1460-9568.2008.06100.X

PubMed Abstract | CrossRef Full Text | Google Scholar

Lucas, J., Connor, E., and Bose, J. (2021). Back, lower limb, and upper limb pain among U.S. Adults, 2019. NCHS Data Brief [Epub ahead of print]. doi: 10.15620/CDC:107894

CrossRef Full Text | Google Scholar

Lueptow, L. M., Fakira, A. K., and Bobeck, E. N. (2018). The contribution of the descending pain modulatory pathway in opioid tolerance. Front. Neurosci. 12:886. doi: 10.3389/fnins.2018.00886

PubMed Abstract | CrossRef Full Text | Google Scholar

Lutfy, K., and Cowan, A. (2004). Buprenorphine: a unique drug with complex pharmacology. Curr. Neuropharmacol. 2:395. doi: 10.2174/1570159043359477

PubMed Abstract | CrossRef Full Text | Google Scholar

Lutfy, K., Do, T., and Maidment, N. T. (2001a). Orphanin FQ/nociceptin attenuates motor stimulation and changes in nucleus accumbens extracellular dopamine induced by cocaine in rats. Psychopharmacology 154, 1–7. doi: 10.1007/s002130000609

PubMed Abstract | CrossRef Full Text | Google Scholar

Lutfy, K., Hossain, S. M., Khaliq, I., and Maidment, N. T. (2001b). Orphanin FQ/nociceptin attenuates the development of morphine tolerance in rats. Br. J. Pharmacol. 134, 529–534. doi: 10.1038/SJ.BJP.0704279

PubMed Abstract | CrossRef Full Text | Google Scholar

Lyness, W. H., Smith, F. L., Heavner, J. E., Iacono, C. U., and Garvin, R. D. (1989). Morphine self-administration in the rat during adjuvant-induced arthritis. Life Sci. 45, 2217–2224. doi: 10.1016/0024-3205(89)90062-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Macey, T. A., Bobeck, E. N., Hegarty, D. M., Aicher, S. A., Ingram, S. L., and Morgan, M. M. (2009). Extracellular signal-regulated kinase 1/2 activation counteracts morphine tolerance in the periaqueductal gray of the rat. J. Pharmacol. Exp. Ther. 331, 412–418. doi: 10.1124/JPET.109.152157

PubMed Abstract | CrossRef Full Text | Google Scholar

Macey, T. A., Lowe, J. D., and Chavkin, C. (2006). Mu Opioid Receptor Activation of ERK1/2 Is GRK3 and arrestin dependent in striatal neurons. J. Biol. Chem. 281, 34515–34524. doi: 10.1074/JBC.M604278200

PubMed Abstract | CrossRef Full Text | Google Scholar

Maher, D. P., Zhang, Y., Ahmed, S., Doshi, T., Malarick, C., Stabach, K., et al. (2017). Chronic opioid therapy modifies QST changes after ketamine infusion in chronic pain patients. J. Pain 18, 1468–1475. doi: 10.1016/J.JPAIN.2017.07.008

PubMed Abstract | CrossRef Full Text | Google Scholar

Makary, M. M., Polosecki, P., Cecchi, G. A., DeAraujo, I. E., Barron, D. S., Constable, T. R., et al. (2020). Loss of nucleus accumbens low-frequency fluctuations is a signature of chronic pain. Proc. Natl. Acad. Sci. U.S.A. 117, 10015–10023. doi: 10.1073/PNAS.1918682117

PubMed Abstract | CrossRef Full Text | Google Scholar

Manchikanti, L., Vanaparthy, R., Atluri, S., Sachdeva, H., Kaye, A. D., and Hirsch, J. A. (2021). COVID-19 and the opioid epidemic: two public health emergencies that intersect with chronic pain. Pain Ther. 10, 269–286. doi: 10.1007/S40122-021-00243-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Manglik, A., Lin, H., Aryal, D. K., McCorvy, J. D., Dengler, D., Corder, G., et al. (2016). Structure-based discovery of opioid analgesics with reduced side effects. Nature 537, 185–190. doi: 10.1038/nature19112

PubMed Abstract | CrossRef Full Text | Google Scholar

Manubay, J., Davidson, J., Vosburg, S., Jones, J., Comer, S., and Sullivan, M. (2015). Sex differences among opioid-abusing chronic pain patients in a clinical trial. J. Addict. Med. 9:46. doi: 10.1097/ADM.0000000000000086

PubMed Abstract | CrossRef Full Text | Google Scholar

Mao, J., Sung, B., Ji, R.-R., and Lim, G. (2002). Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity. J. Neurosci. 22, 8312–8323. doi: 10.1523/JNEUROSCI.22-18-08312.2002

PubMed Abstract | CrossRef Full Text | Google Scholar

Marchand, S. (2008). The physiology of pain mechanisms: from the periphery to the brain. Rheum. Dis. Clin. North Am. 34, 285–309. doi: 10.1016/J.RDC.2008.04.003

PubMed Abstract | CrossRef Full Text | Google Scholar

Mark, T. L., and Parish, W. (2019). Opioid medication discontinuation and risk of adverse opioid-related health care events. J. Subst. Abuse Treat. 103, 58–63. doi: 10.1016/j.jsat.2019.05.001

PubMed Abstract | CrossRef Full Text | Google Scholar

Markovic, T., Pedersen, C. E., Massaly, N., Vachez, Y. M., Ruyle, B., Murphy, C. A., et al. (2021). Pain induces adaptations in ventral tegmental area dopamine neurons to drive anhedonia-like behavior. Nat. Neurosci. 24, 1601–1613. doi: 10.1038/s41593-021-00924-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Martikainen, I. K., Nuechterlein, E. B., Peciña, M., Love, T. M., Cummiford, C. M., Green, C. R., et al. (2015). Chronic back pain is associated with alterations in dopamine neurotransmission in the ventral striatum. J. Neurosci. 35, 9957–9965. doi: 10.1523/JNEUROSCI.4605-14.2015

PubMed Abstract | CrossRef Full Text | Google Scholar

Martikainen, I. K., Peciña, M., Love, T. M., Nuechterlein, E. B., Cummiford, C. M., Green, C. R., et al. (2013). Alterations in endogenous opioid functional measures in chronic back pain. J. Neurosci. 33, 14729–14737. doi: 10.1523/JNEUROSCI.1400-13.2013

PubMed Abstract | CrossRef Full Text | Google Scholar

Martin, T. J., Kim, S. A., Buechler, N. L., Porreca, F., and Eisenach, J. C. (2007). Opioid Self-administration in the nerve-injured ratrelevance of antiallodynic effects to drug consumption and effects of intrathecal analgesics. Anesthesiology 106, 312–322. doi: 10.1097/00000542-200702000-00020

PubMed Abstract | CrossRef Full Text | Google Scholar

Martin, T. J., Kim, S. A., and Eisenach, J. C. (2006). Clonidine maintains intrathecal self-administration in rats following spinal nerve ligation. Pain 125, 257–263. doi: 10.1016/J.PAIN.2006.05.027

PubMed Abstract | CrossRef Full Text | Google Scholar

Martin, W. R., Eades, C. G., Thompson, J. A., Huppler, R. E., and Gilbert, P. E. (1976). The effects of morphine and nalorphine like drugs in the nondependent and morphine dependent chronic spinal dog. J. Pharmacol. Exp. Ther. 197, 517–532.

Google Scholar

Massaly, N., Copits, B. A., Wilson-Poe, A. R., Hipólito, L., Markovic, T., Yoon, H. J., et al. (2019). Pain-induced negative affect is mediated via recruitment of the nucleus accumbens kappa opioid system. Neuron 102, 564.e6–573.e6. doi: 10.1016/j.neuron.2019.02.029

PubMed Abstract | CrossRef Full Text | Google Scholar

Massaly, N., Markovic, T., Creed, M., Al-Hasani, R., Cahill, C. M., and Moron, J. A. (2021). Pain, negative affective states and opioid-based analgesics: safer pain therapies to dampen addiction. Int. Rev. Neurobiol. 157, 31–68. doi: 10.1016/BS.IRN.2020.09.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Massaly, N., and Morón, J. A. (2019). Pain and opioid systems, implications in the opioid epidemic. Curr. Opin. Behav. Sci. 26, 69–74. doi: 10.1016/j.cobeha.2018.10.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Massaly, N., Temp, J., Machelska, H., and Stein, C. (2020). Uncovering the analgesic effects of a pH-dependent mu-opioid receptor agonist using a model of nonevoked ongoing pain. Pain 161, 2798–2804. doi: 10.1097/J.PAIN.0000000000001968

PubMed Abstract | CrossRef Full Text | Google Scholar

Matsui, A., Jarvie, B. C., Robinson, B. G., Hentges, S. T., and Williams, J. T. (2014). Separate GABA afferents to dopamine neurons mediate acute action of opioids, development of tolerance, and expression of withdrawal. Neuron 82, 1346–1356. doi: 10.1016/J.NEURON.2014.04.030

PubMed Abstract | CrossRef Full Text | Google Scholar

Mattick, R. P., Breen, C., Kimber, J., and Davoli, M. (2009). Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst. Rev. 3:CD002209. doi: 10.1002/14651858.CD002209.pub2

PubMed Abstract | CrossRef Full Text | Google Scholar

McHugh, R. K. (2020). The importance of studying sex and gender differences in opioid misuse. JAMA Netw. Open 3:e2030676. doi: 10.1001/JAMANETWORKOPEN.2020.30676

PubMed Abstract | CrossRef Full Text | Google Scholar

Meisenberg, B. R., Grover, J., Campbell, C., and Korpon, D. (2018). Assessment of opioid prescribing practices before and after implementation of a health system intervention to reduce opioid overprescribing. JAMA Netw. Open 1:e182908. doi: 10.1001/jamanetworkopen.2018.2908

PubMed Abstract | CrossRef Full Text | Google Scholar

Meunier, J. C., Mollereau, C., Toll, L., Suaudeau, C., Moisand, C., Alvinerie, P., et al. (1995). Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature 377, 532–535. doi: 10.1038/377532a0

PubMed Abstract | CrossRef Full Text | Google Scholar

Meyer, P. J., Fossum, E. N., Ingram, S. L., and Morgan, M. M. (2007). Analgesic tolerance to microinjection of the μ-opioid agonist DAMGO into the ventrolateral periaqueductal gray. Neuropharmacology 52, 1580–1585. doi: 10.1016/J.NEUROPHARM.2007.03.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Millan, M. H. J., Millan, M. H. J., Pilcher, C. W. T., Cz, L. A., Herz, A., and Colpaert, F. C. (1985). Spinal cord dynorphin may modulate nociception via a kappa-opioid receptor in chronic arthritic rats. Brain Res. 340, 156–159. doi: 10.1016/0006-8993(85)90786-3

CrossRef Full Text | Google Scholar

Millan, M. J., Członkowski, A., Morris, B., Stein, C., Arendt, R., Huber, A., et al. (1988). Inflammation of the hind limb as a model of unilateral, localized pain: influence on multiple opioid systems in the spinal cord of the rat. Pain 35, 299–312. doi: 10.1016/0304-3959(88)90140-6

CrossRef Full Text | Google Scholar

Millan, M. J., Czlonkowski, A., Pilcher, C. W. T., Almeida, O. F. X., Millan, M. H., Colpaert, F. C., et al. (1987). A model of chronic pain in the rat: functional correlates of alterations in the activity of opioid systems. J. Neurosci. 7, 77–87. doi: 10.1523/jneurosci.07-01-00077.1987

PubMed Abstract | CrossRef Full Text | Google Scholar

Minozzi, S., Amato, L., and Davoli, M. (2013). Development of dependence following treatment with opioid analgesics for pain relief: a systematic review. Addiction 108, 688–698. doi: 10.1111/J.1360-0443.2012.04005.X

PubMed Abstract | CrossRef Full Text | Google Scholar

Mitsi, V., and Zachariou, V. (2016). Modulation of pain, nociception, and analgesia by the brain reward center. Neuroscience 338, 81–92.

Google Scholar

Mittal, N., Roberts, K., Pal, K., Bentolila, L. A., Fultz, E., Minasyan, A., et al. (2013). Select G-protein-coupled receptors modulate agonist-induced signaling via a ROCK, LIMK, and β-arrestin 1 pathway. Cell Rep. 5, 1010–1021. doi: 10.1016/J.CELREP.2013.10.015

PubMed Abstract | CrossRef Full Text | Google Scholar

Miyata, H., Takahashi, M., Murai, Y., Tsuneyoshi, K., Hayashi, T., Meulien, D., et al. (2019). Nalmefene in alcohol-dependent patients with a high drinking risk: randomized controlled trial. Psychiatry Clin. Neurosci. 73, 697–706. doi: 10.1111/PCN.12914

PubMed Abstract | CrossRef Full Text | Google Scholar

Mogil, J. S. (2012). Pain genetics: past, present and future. Trends Genet. 28, 258–266. doi: 10.1016/J.TIG.2012.02.004

PubMed Abstract | CrossRef Full Text | Google Scholar

Mogil, J. S., Grisel, J. E., Reinscheid, R. K., Civelli, O., Belknap, J. K., and Grandy, D. K. (1996a). Orphanin FQ is a functional anti-opioid peptide. Neuroscience 75, 333–337. doi: 10.1016/0306-4522(96)00338-7

CrossRef Full Text | Google Scholar

Mogil, J. S., Grisel, J. E., Zhangs, G., Belknap, J. K., and Grandy, D. K. (1996b). Functional antagonism of μ-, δ- and κ-opioid antinociception by orphanin FQ. Neurosci. Lett. 214, 131–134. doi: 10.1016/0304-3940(96)12917-7

CrossRef Full Text | Google Scholar

Mohammadkhani, A., and Borgland, S. L. (2022). Cellular and behavioral basis of cannabinioid and opioid interactions: implications for opioid dependence and withdrawal. J. Neurosci. Res. 100, 278–296. doi: 10.1002/jnr.24770

PubMed Abstract | CrossRef Full Text | Google Scholar

Mollereau, C., Parmentier, M., Mailleux, P., Butour, J. L., Moisand, C., Chalon, P., et al. (1994). ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization. FEBS Lett. 341, 33–38.

Google Scholar

Morasco, B. J., Gritzner, S., Lewis, L., Oldham, R., Turk, D. C., and Dobscha, S. K. (2011). Systematic review of prevalence, correlates, and treatment outcomes for chronic non-cancer pain in patients with comorbid substance use disorder. Pain 152, 488–497. doi: 10.1016/J.PAIN.2010.10.009

PubMed Abstract | CrossRef Full Text | Google Scholar

Morgan, D. O. (1997). Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu. Rev. Cell Dev. Biol. 13, 261–291. doi: 10.1146/ANNUREV.CELLBIO.13.1.261

PubMed Abstract | CrossRef Full Text | Google Scholar

Morgan, M. M., Fossum, E. N., Levine, C. S., and Ingram, S. L. (2006). Antinociceptive tolerance revealed by cumulative intracranial microinjections of morphine into the periaqueductal gray in the rat. Pharmacol. Biochem. Behav. 85, 214–219. doi: 10.1016/J.PBB.2006.08.003

PubMed Abstract | CrossRef Full Text | Google Scholar

Morinville, A., Cahill, C. M., Aibak, H., Rymar, V. V., Pradhan, A., Hoffert, C., et al. (2004a). Morphine-induced changes in delta opioid receptor trafficking are linked to somatosensory processing in the rat spinal cord. J. Neurosci. 24, 5549–5559. doi: 10.1523/JNEUROSCI.2719-03.2004

PubMed Abstract | CrossRef Full Text | Google Scholar

Morinville, A., Cahill, C. M., Kieffer, B., Collier, B., and Beaudet, A. (2004b). Mu-opioid receptor knockout prevents changes in delta-opioid receptor trafficking induced by chronic inflammatory pain. Pain 109, 266–273. doi: 10.1016/j.pain.2004.01.011

PubMed Abstract | CrossRef Full Text | Google Scholar

Morone, N. E., and Weiner, D. K. (2013). Pain as the fifth vital sign: exposing the vital need for pain education. Clin. Ther. 35, 1728–1732. doi: 10.1016/j.clinthera.2013.10.001

PubMed Abstract | CrossRef Full Text | Google Scholar

Moulédous, L. (2019). The nociceptin / orphanin FQ system and the regulation of memory. Handb. Exp. Pharmacol. 254, 259–278.

Google Scholar

Moye, L. S., Siegersma, K., Dripps, I., Witkowski, W., Mangutov, E., Wang, D., et al. (2021). Delta opioid receptor regulation of calcitonin gene-related peptide dynamics in the trigeminal complex. Pain 162, 2297–2308. doi: 10.1097/J.PAIN.0000000000002235

PubMed Abstract | CrossRef Full Text | Google Scholar

Murakawa, K., Hirose, N., Takada, K., Suzuki, T., Nagase, H., Cools, A. R., et al. (2004). Deltorphin II enhances extracellular levels of dopamine in the nucleus accumbens via opioid receptor-independent mechanisms. Eur. J. Pharmacol. 491, 31–36. doi: 10.1016/j.ejphar.2004.03.028

PubMed Abstract | CrossRef Full Text | Google Scholar

Murphy, N. P., Ly, H. T., and Maidment, N. T. (1996). Intracerebroventricular orphanin FQ/nociceptin suppresses dopamine release in the nucleus accumbens of anaesthetized rats. Neuroscience 75, 1–4. doi: 10.1016/0306-4522(96)00322-3

CrossRef Full Text | Google Scholar

Nadeau, S. E., Wu, J. K., and Lawhern, R. A. (2021). Opioids and chronic pain: an analytic review of the clinical evidence. Front. Pain Res. 2:721357. doi: 10.3389/FPAIN.2021.721357

PubMed Abstract | CrossRef Full Text | Google Scholar

Nakanishi, S., Inoue, A., Kita, T., Inoue, A., Nakamura, M., Chang, A. C. Y., et al. (1979). Nucleotide sequence of cloned cDNA for bovine corticotropin-β- lipotropin precursor. Nature 278, 423–427. doi: 10.1038/278423a0

PubMed Abstract | CrossRef Full Text | Google Scholar

Namba, M. D., Leyrer-Jackson, J. M., Nagy, E. K., Olive, M. F., and Neisewander, J. L. (2021). Neuroimmune mechanisms as novel treatment targets for substance use disorders and associated comorbidities. Front. Neurosci. 15:427. doi: 10.3389/FNINS.2021.650785/BIBTEX

CrossRef Full Text | Google Scholar

Narita, M., Kaneko, C., Miyoshi, K., Nagumo, Y., Kuzumaki, N., Nakajima, M., et al. (2006a). Chronic pain induces anxiety with concomitant changes in opioidergic function in the amygdala. Neuropsychopharmacology 31, 739–750. doi: 10.1038/SJ.NPP.1300858

PubMed Abstract | CrossRef Full Text | Google Scholar

Narita, M., Kuzumaki, N., Narita, M., Kaneko, C., Hareyama, N., Miyatake, M., et al. (2006b). Chronic pain-induced emotional dysfunction is associated with astrogliosis due to cortical δ-opioid receptor dysfunction. J. Neurochem. 97, 1369–1378. doi: 10.1111/J.1471-4159.2006.03824.X

PubMed Abstract | CrossRef Full Text | Google Scholar

Narita, M., Kishimoto, Y., Ise, Y., Yajima, Y., Misawa, K., and Suzuki, T. (2005). Direct evidence for the involvement of the mesolimbic κ-opioid system in the morphine-induced rewarding effect under an inflammatory pain-like state. Neuropsychopharmacology 30, 111–118. doi: 10.1038/sj.npp.1300527

PubMed Abstract | CrossRef Full Text | Google Scholar

Navratilova, E., Atcherley, C. W., and Porreca, F. (2015). Brain circuits encoding reward from pain relief. Trends Neurosci. 38, 741–750. doi: 10.1016/J.TINS.2015.09.003

PubMed Abstract | CrossRef Full Text | Google Scholar

Navratilova, E., Ji, G., Phelps, C., Qu, C., Hein, M., Yakhnitsa, V., et al. (2019). Kappa opioid signaling in the central nucleus of the amygdala promotes disinhibition and aversiveness of chronic neuropathic pain. Pain 160, 824–832. doi: 10.1097/J.PAIN.0000000000001458

PubMed Abstract | CrossRef Full Text | Google Scholar

Nguyen, D., Alushaj, E., Erb, S., and Ito, R. (2019). Dissociative effects of dorsomedial striatum D1 and D2 receptor antagonism in the regulation of anxiety and learned approach-avoidance conflict decision-making. Neuropharmacology 146, 222–230. doi: 10.1016/j.neuropharm.2018.11.040

PubMed Abstract | CrossRef Full Text | Google Scholar

NIDA (2008). Comorbidity: Addiction and Other Mental Illnesses. Bethesda, MD: NIDA.

Google Scholar

Niikura, K., Narita, M., Butelman, E. R., Kreek, M. J., and Suzuki, T. (2010). Neuropathic and chronic pain stimuli downregulate central μ -opioid and dopaminergic transmission. Trends Pharmacol. Sci. 31, 299–305. doi: 10.1016/J.TIPS.2010.04.003

PubMed Abstract | CrossRef Full Text | Google Scholar

Niikura, K., Narita, M., Narita, M., Nakamura, A., Okutsu, D., Ozeki, A., et al. (2008). Direct evidence for the involvement of endogenous β-endorphin in the suppression of the morphine-induced rewarding effect under a neuropathic pain-like state. Neurosci. Lett. 435, 257–262. doi: 10.1016/J.NEULET.2008.02.059

PubMed Abstract | CrossRef Full Text | Google Scholar

Normandin, A., Luccarini, P., Molat, J. L., Gendron, L., and Dallel, R. (2013). Spinal μ and δ opioids inhibit both thermal and mechanical pain in rats. J. Neurosci. 33, 11703–11714. doi: 10.1523/JNEUROSCI.1631-13.2013

PubMed Abstract | CrossRef Full Text | Google Scholar

Nylander, I., Vlaskovska, M., and Terenius, L. (1995). Brain dynorphin and enkephalin systems in Fischer and Lewis rats: effects of morphine tolerance and withdrawal. Brain Res. 683, 25–35. doi: 10.1016/0006-8993(95)00279-Y

CrossRef Full Text | Google Scholar

Olson, G. A., Olson, R. D., Kastin, A. J., and Coy, D. H. (1979). Endogenous opiates: through 1978. Neurosci. Biobehav. Rev. 3, 285–299. doi: 10.1016/0149-7634(79)90014-9

CrossRef Full Text | Google Scholar

Ozaki, S., Narita, M., Narita, M., Iino, M., Miyoshi, K., and Suzuki, T. (2003). Suppression of the morphine-induced rewarding effect and G-protein activation in the lower midbrain following nerve injury in the mouse: involvement of G-protein-coupled receptor kinase 2. Neuroscience 116, 89–97. doi: 10.1016/S0306-4522(02)00699-1

CrossRef Full Text | Google Scholar

Ozaki, S., Narita, M., Narita, M., Ozaki, M., Khotib, J., and Suzuki, T. (2004). Role of extracellular signal-regulated kinase in the ventral tegmental area in the suppression of the morphine-induced rewarding effect in mice with sciatic nerve ligation. J. Neurochem. 88, 1389–1397. doi: 10.1046/J.1471-4159.2003.02272.X

PubMed Abstract | CrossRef Full Text | Google Scholar

Ozaki, S., Narita, M. M., Narita, M. M., Iino, M., Sugita, J., Matsumura, Y., et al. (2002). Suppression of the morphine-induced rewarding effect in the rat with neuropathic pain: implication of the reduction in l-opioid receptor functions in the ventral tegmental area. J. Neurochem. 82, 1192–1198. doi: 10.1046/J.1471-4159.2002.01071.X

PubMed Abstract | CrossRef Full Text | Google Scholar

Parida, S., Carroll, K. M., Petrakis, I. L., and Sofuoglu, M. (2019). Buprenorphine treatment for opioid use disorder: recent progress. Expert Rev. Clin. Pharmacol. 12, 791–803. doi: 10.1080/17512433.2019.1635454

PubMed Abstract | CrossRef Full Text | Google Scholar

Pathan, H., and Williams, J. (2012). Basic opioid pharmacology: an update. Br. J. Pain 6:11. doi: 10.1177/2049463712438493

PubMed Abstract | CrossRef Full Text | Google Scholar

Peciña, M., Karp, J. F., Mathew, S., Todtenkopf, M. S., Ehrich, E. W., and Zubieta, J. K. (2018). Endogenous opioid system dysregulation in depression: implications for new therapeutic approaches. Mol. Psychiatry 24, 576–587. doi: 10.1038/s41380-018-0117-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Peng, J., Sarkar, S., and Chang, S. L. (2012). Opioid receptor expression in human brain and peripheral tissues using absolute quantitative real-time RT-PCR. Drug Alcohol. Depend. 124, 223–228. doi: 10.1016/J.DRUGALCDEP.2012.01.013

PubMed Abstract | CrossRef Full Text | Google Scholar

Pereira, F. G., França, M. H., de Paiva, M. C. A., Andrade, L. H., and Viana, M. C. (2017). Prevalence and clinical profile of chronic pain and its association with mental disorders. Rev. Saude Publ. 51:96. doi: 10.11606/S1518-8787.2017051007025

PubMed Abstract | CrossRef Full Text | Google Scholar

Pergolizzi, J. Jr., and Raffa, R. (2019). Safety and efficacy of the unique opioid buprenorphine for the treatment of chronic pain. J. Pain Res. 12, 3299–3317. doi: 10.2147/JPR.S231948

PubMed Abstract | CrossRef Full Text | Google Scholar

Perrine, S. A., Hoshaw, B. A., and Unterwald, E. M. (2006). Delta opioid receptor ligands modulate anxiety-like behaviors in the rat. Br. J. Pharmacol. 147, 864–872. doi: 10.1038/SJ.BJP.0706686

PubMed Abstract | CrossRef Full Text | Google Scholar

Pert, C. B., and Snyder, S. H. (1973). Opiate receptor: demonstration in nervous tissue. Science 179, 1011–1014. doi: 10.1126/SCIENCE.179.4077.1011

PubMed Abstract | CrossRef Full Text | Google Scholar

Petraschka, M., Li, S., Gilbert, T. L., Westenbroek, R. E., Bruchas, M. R., Schreiber, S., et al. (2007). The absence of endogenous beta-endorphin selectively blocks phosphorylation and desensitization of mu opioid receptors following partial sciatic nerve ligation. Neuroscience 146, 1795–1807. doi: 10.1016/J.NEUROSCIENCE.2007.03.029

PubMed Abstract | CrossRef Full Text | Google Scholar

Pfeiffer, A., Brantl, V., Herz, A., and Emrich, H. M. (1986). Psychotomimesis mediated by kappa opiate receptors. Science 233, 774–776. doi: 10.1126/SCIENCE.3016896

PubMed Abstract | CrossRef Full Text | Google Scholar

Pignatelli, M., and Bonci, A. (2015). Role of dopamine neurons in reward and aversion: a synaptic plasticity perspective. Neuron 86, 1145–1157. doi: 10.1016/j.neuron.2015.04.015

PubMed Abstract | CrossRef Full Text | Google Scholar

Pisanu, C., Franconi, F., Gessa, G. L., Mameli, S., Pisanu, G. M., Campesi, I., et al. (2019). Sex differences in the response to opioids for pain relief: a systematic review and meta-analysis. Pharmacol. Res. 148:104447. doi: 10.1016/J.PHRS.2019.104447

PubMed Abstract | CrossRef Full Text | Google Scholar

Podvin, S., Yaksh, T., and Hook, V. (2016). The emerging role of spinal dynorphin in chronic pain: a therapeutic perspective. Annu. Rev. Pharmacol. Toxicol. 56, 511–533. doi: 10.1146/annurev-pharmtox-010715-103042

PubMed Abstract | CrossRef Full Text | Google Scholar

Pol, O., Murtra, P., Caracuel, L., Valverde, O., Puig, M. M., and Maldonado, R. (2006). Expression of opioid receptors and c-fos in CB1 knockout mice exposed to neuropathic pain. Neuropharmacology 50, 123–132. doi: 10.1016/J.NEUROPHARM.2005.11.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Porreca, F., Tang, Q. B., Bian, D., Riedl, M., Eide, R., and Lai, J. (1998). Spinal opioid mu receptor expression in lumbar spinal cord of rats following nerve injury. Brain Res. 795, 197–203. doi: 10.1016/S0006-8993(98)00292-3

CrossRef Full Text | Google Scholar

Pradhan, A. A., Befort, K., Nozaki, C., Gavériaux-Ruff, C., and Kieffer, B. L. (2011). The delta opioid receptor: an evolving target for the treatment of brain disorders. Trends Pharmacol. Sci. 32, 581–590. doi: 10.1016/J.TIPS.2011.06.008

PubMed Abstract | CrossRef Full Text | Google Scholar

Przewlocki, R. (2004). Opioid abuse and brain gene expression. Eur. J. Pharmacol. 500, 331–349. doi: 10.1016/J.EJPHAR.2004.07.036

PubMed Abstract | CrossRef Full Text | Google Scholar

Quirion, B., Bergeron, F., Blais, V., and Gendron, L. (2020). The delta-opioid receptor; a target for the treatment of pain. Front. Mol. Neurosci. 13:52. doi: 10.3389/fnmol.2020.00052

PubMed Abstract | CrossRef Full Text | Google Scholar

Raehal, K. M., Schmid, C. L., Groer, C. E., and Bohn, L. M. (2011). Functional selectivity at the μ-opioid receptor: implications for understanding opioid analgesia and tolerance. Pharmacol. Rev. 63, 1001–1019. doi: 10.1124/pr.111.004598

PubMed Abstract | CrossRef Full Text | Google Scholar

Raffa, R. B., Martinez, R. P., and Connelly, C. D. (1994). G-protein antisense oligodeoxyribonucleotides and μ-opioid supraspinal antinociception. Eur. J. Pharmacol. 258, R5–R7. doi: 10.1016/0014-2999(94)90073-6

CrossRef Full Text | Google Scholar

Raghavendra, V., Rutkowski, M. D., and Deleo, J. A. (2002). The role of spinal neuroimmune activation in morphine tolerance/hyperalgesia in neuropathic and sham-operated rats. J. Neurosci. 22, 9980–9989. doi: 10.1523/JNEUROSCI.22-22-09980.2002

PubMed Abstract | CrossRef Full Text | Google Scholar

Raja, S. N., Carr, D. B., Cohen, M., Finnerup, N. B., Flor, H., Gibson, S., et al. (2020). The Revised IASP definition of pain: concepts, challenges, and compromises. Pain 161:1976. doi: 10.1097/J.PAIN.0000000000001939

PubMed Abstract | CrossRef Full Text | Google Scholar

Ranganathan, M., Schnakenberg, A., Skosnik, P. D., Cohen, B. M., Pittman, B., Sewell, R. A., et al. (2012). Dose-related behavioral, subjective, endocrine, and psychophysiological effects of the κ opioid agonist Salvinorin A in humans. Biol. Psychiatry 72, 871–879. doi: 10.1016/J.BIOPSYCH.2012.06.012

PubMed Abstract | CrossRef Full Text | Google Scholar

Rashid, H., Inoue, M., Toda, K., and Ueda, H. (2004). Loss of peripheral morphine analgesia contributes to the reduced effectiveness of systemic morphine in neuropathic pain. J. Pharmacol. Exp. Ther. 309, 380–387. doi: 10.1124/JPET.103.060582

PubMed Abstract | CrossRef Full Text | Google Scholar

Reiner, D. J., Fredriksson, I., Lofaro, O. M., Bossert, J. M., and Shaham, Y. (2019). Relapse to opioid seeking in rat models: behavior, pharmacology and circuits. Neuropsychopharmacology 44, 465–477. doi: 10.1038/s41386-018-0234-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Reiner, D. J., Townsend, E. A., Orihuel, J., Applebey, S. V., Claypool, S. M., Banks, M. L., et al. (2021). Lack of effect of different pain-related manipulations on opioid self-administration, reinstatement of opioid seeking, and opioid choice in rats. Psychopharmacology 238, 1885–1897. doi: 10.1007/S00213-021-05816-9/FIGURES/5

CrossRef Full Text | Google Scholar

Reinscheid, R. K., Nothacker, H. P., Bourson, A., Ardati, A., Henningsen, R. A., Bunzow, J. R., et al. (1995). Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor. Science 270, 792–794.

Google Scholar

Reiss, D., Maurin, H., Audouard, E., Martínez-Navarro, M., Xue, Y., Herault, Y., et al. (2021). Delta opioid receptor in astrocytes contributes to neuropathic cold pain and analgesic tolerance in female mice. Front. Cell Neurosci. 15:745178. doi: 10.3389/FNCEL.2021.745178/FULL

PubMed Abstract | CrossRef Full Text | Google Scholar

Remesic, M., Hruby, V. J., Porreca, F., and Lee, Y. S. (2017). Recent advances in the realm of allosteric modulators for opioid receptors for future therapeutics. ACS Chem. Neurosci. 8, 1147–1158. doi: 10.1021/ACSCHEMNEURO.7B00090

PubMed Abstract | CrossRef Full Text | Google Scholar

Ren, W., Centeno, M. V., Berger, S., Wu, Y., Na, X., Liu, X., et al. (2015). The indirect pathway of the nucleus accumbens shell amplifies neuropathic pain. Nat. Neurosci. 19, 220–222. doi: 10.1038/nn.4199

PubMed Abstract | CrossRef Full Text | Google Scholar

Ren, W., Centeno, M. V., Wei, X., Wickersham, I., Martina, M., Apkarian, A. V., et al. (2021). Adaptive alterations in the mesoaccumbal network after peripheral nerve injury. Pain 162, 895–906. doi: 10.1097/J.PAIN.0000000000002092

PubMed Abstract | CrossRef Full Text | Google Scholar

Rhodin, A., Grönbladh, A., Ginya, H., Nilsson, K. W., Rosenblad, A., Zhou, Q., et al. (2013). Combined analysis of circulating β-endorphin with gene polymorphisms in OPRM1, CACNAD2 and ABCB1 reveals correlation with pain, opioid sensitivity and opioid-related side effects. Mol. Brain 6:8. doi: 10.1186/1756-6606-6-8

PubMed Abstract | CrossRef Full Text | Google Scholar

Ringkamp, M., Dougherty, P. M., and Raja, S. N. (2018). Anatomy and physiology of the pain signaling process. Essent. Pain Med. 2018, 3.e1–10.e1. doi: 10.1016/B978-0-323-40196-8.00001-2

CrossRef Full Text | Google Scholar

Rizvi, S. J., Gandhi, W., and Salomons, T. (2021). Reward processing as a common diathesis for chronic pain and depression. Neurosci. Biobehav. Rev. 127, 749–760. doi: 10.1016/J.NEUBIOREV.2021.04.033

PubMed Abstract | CrossRef Full Text | Google Scholar

Rizzi, A., Bigoni, R., Marzola, G., Guerrini, R., Salvadori, S., Regoli, D., et al. (2001). Characterization of the locomotor activity-inhibiting effect of nociceptin/orphanin FQ in mice. Naunyn Schmiedebergs Arch. Pharmacol. 363, 161–165. doi: 10.1007/s002100000358

PubMed Abstract | CrossRef Full Text | Google Scholar

Rizzi, A., Gavioli, E., Marzola, G., Spagnolo, B., Zucchini, S., Ciccocioppo, R., et al. (2007). Pharmacological characterization of the nociceptin/orphanin FQ receptor antagonist SB-612111 [(–)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol]: in vivo studies. J. Pharmacol. Exp. Ther. 321, 968–974.

Google Scholar

Rizzi, A., Molinari, S., Marti, M., Marzola, G., and Calo’, G. (2011). Nociceptin/orphanin FQ receptor knockout rats: in vitro and in vivo studies. Neuropharmacology 60, 572–579. doi: 10.1016/J.NEUROPHARM.2010.12.010

PubMed Abstract | CrossRef Full Text | Google Scholar

Roeckel, L. A., le Coz, G. M., Gavériaux-Ruff, C., and Simonin, F. (2016). Opioid-induced hyperalgesia: cellular and molecular mechanisms. Neuroscience 338, 160–182. doi: 10.1016/j.neuroscience.2016.06.029

PubMed Abstract | CrossRef Full Text | Google Scholar

Rogers, A. H., Manning, K., Garey, L., Smit, T., and Zvolensky, M. J. (2020). Sex differences in the relationship between anxiety sensitivity and opioid misuse among adults with chronic pain. Addict. Behav. 102:106156. doi: 10.1016/J.ADDBEH.2019.106156

PubMed Abstract | CrossRef Full Text | Google Scholar

Rudd, R. A., Aleshire, N., Zibbell, J. E., and Gladden, R. M. (2016). Increases in drug and opioid overdose deaths—United States, 2000–14. Morb. Mortal Wkly Rep. 64, 1378–1382. doi: 10.15585/mmwr.mm6450a3

PubMed Abstract | CrossRef Full Text | Google Scholar

Saegusa, H., Kurihara, T., Zong, S., Minowa, O., Kazuno, A.-A., Han, W., et al. (2000). Altered Pain Responses in Mice Lacking 1E Subunit of the Voltage-Dependent Ca 2 Channel. Stanford, CA: Stanford University School of Medicine.

Google Scholar

Saigusa, T., Aono, Y., and Waddington, J. L. (2017). Mechanisms underlying δ- and μ-opioid receptor agonist-induced increases in extracellular dopamine level in the nucleus accumbens of freely moving rats. J. Oral Sci. 59, 195–200. doi: 10.2334/josnusd.16-0874

PubMed Abstract | CrossRef Full Text | Google Scholar

Saitoh, A., Yoshikawa, Y., Onodera, K., and Kamei, J. (2005). Role of δ-opioid receptor subtypes in anxiety-related behaviors in the elevated plus-maze in rats. Psychopharmacology 182, 327–334. doi: 10.1007/S00213-005-0112-6

PubMed Abstract | CrossRef Full Text | Google Scholar

Sakoori, K., and Murphy, N. P. (2004). Central administration of nociceptin/orphanin FQ blocks the acquisition of conditioned place preference to morphine and cocaine, but not conditioned place aversion to naloxone in mice. Psychopharmacology 172, 129–136. doi: 10.1007/S00213-003-1643-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Samuelsonn, H., Ekman, R., and Hedner, T. (1993). CSF neuropeptides in cancer pain: effects of spinal opioid therapy. Acta Anaesthesiol. Scand. 37, 502–508. doi: 10.1111/J.1399-6576.1993.TB03755.X

PubMed Abstract | CrossRef Full Text | Google Scholar

Schlosburg, J. E., Whitfield, T. W., Park, P. E., Crawford, E. F., George, O., Vendruscolo, L. F., et al. (2013). Long-term antagonism of κ opioid receptors prevents escalation of and increased motivation for heroin intake. J. Neurosci. 33, 19384–19392. doi: 10.1523/JNEUROSCI.1979-13.2013

PubMed Abstract | CrossRef Full Text | Google Scholar

Schrepf, A., Harper, D. E., Harte, S. E., Wang, H., Ichesco, E., Hampson, J. P., et al. (2016). Endogenous opioidergic dysregulation of pain in fibromyalgia: a PET and fMRI study. Pain 157, 2217–2225. doi: 10.1097/J.PAIN.0000000000000633

PubMed Abstract | CrossRef Full Text | Google Scholar

Schwartz, N., Temkin, P., Jurado, S., Lim, B. K., Heifets, B. D., Polepalli, J. S., et al. (2014). Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens. Science 345, 535–542. doi: 10.1126/science.1253994

PubMed Abstract | CrossRef Full Text | Google Scholar

Scoto, G. M., Aricò, G., Iemolo, A., Ronsisvalle, G., and Parenti, C. (2010). Selective inhibition of the NOP receptor in the ventrolateral periaqueductal gray attenuates the development and the expression of tolerance to morphine-induced antinociception in rats. Peptides 31, 696–700. doi: 10.1016/j.peptides.2009.12.028

PubMed Abstract | CrossRef Full Text | Google Scholar

Selley, D. E., Lazenka, M. F., Sim-Selley, L. J., Secor McVoy, J. R., Potter, D. N., Chartoff, E. H., et al. (2020). Attenuated dopamine receptor signaling in nucleus accumbens core in a rat model of chemically-induced neuropathy. Neuropharmacology 166:107935. doi: 10.1016/J.NEUROPHARM.2020.107935

PubMed Abstract | CrossRef Full Text | Google Scholar

Shen, C. H., Tsai, R. Y., Shih, M. S., Lin, S. L., Tai, Y. H., Chien, C. C., et al. (2011). Etanercept restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in morphine-tolerant rats. Anesth. Analg. 112, 454–459. doi: 10.1213/ANE.0B013E3182025B15

PubMed Abstract | CrossRef Full Text | Google Scholar

Shenoy, S. S., and Lui, F. (2018). Biochemistry, Endogenous Opioids. Treasure Island, FL: StatPearls Publishing.

Google Scholar

Shi, J., Zhao, L. Y., Copersino, M. L., Fang, Y. X., Chen, Y., Tian, J., et al. (2008). PET imaging of dopamine transporter and drug craving during methadone maintenance treatment and after prolonged abstinence in heroin users. Eur. J. Pharmacol. 579, 160–166. doi: 10.1016/J.EJPHAR.2007.09.042

PubMed Abstract | CrossRef Full Text | Google Scholar

Shimoyama, N., Shimoyama, M., Elliott, K. J., and Inturrisi, C. E. (1997). d-methadone is antinociceptive in the rat formalin test. J. Pharmacol. Exp. Ther. 283, 648–652.

Google Scholar

Shoblock, J. R., Wichmann, J., and Maidment, N. T. (2005). The effect of a systemically active ORL-1 agonist, Ro 64-6198, on the acquisition, expression, extinction, and reinstatement of morphine conditioned place preference. Neuropharmacology 49, 439–446. doi: 10.1016/J.NEUROPHARM.2005.04.008

PubMed Abstract | CrossRef Full Text | Google Scholar

Shulman, M., Luo, S. X., Campbell, A. N. C., Scodes, J., Pavlicova, M., Broffman, A., et al. (2020). Secondary analysis of pain outcomes in a large pragmatic randomized trial of buprenorphine/naloxone versus methadone for opioid use disorder. J. Addict. Med. 14, e188–e194. doi: 10.1097/ADM.0000000000000630

PubMed Abstract | CrossRef Full Text | Google Scholar

Silverman, S. M. (2009). Opioid induced hyperalgesia: clinical implications for the pain practitioner. Pain Phys. 12, 679–684. doi: 10.36076/ppj.2009/12/679

CrossRef Full Text | Google Scholar

Simon, E. J., Hiller, J. M., and Edelman, I. (1973). Stereospecific binding of the potent narcotic analgesic [3H] etorphine to rat brain homogenate (opiate receptor/morphine/antagonist). Proc. Natl. Acad. Sci. U.S.A. 70, 1947–1949. doi: 10.1073/pnas.70.7.1947

PubMed Abstract | CrossRef Full Text | Google Scholar

Siuda, E. R., Carr, R., Rominger, D. H., and Violin, J. D. (2017). Biased mu-opioid receptor ligands: a promising new generation of pain therapeutics. Curr. Opin. Pharmacol. 32, 77–84. doi: 10.1016/j.coph.2016.11.007

PubMed Abstract | CrossRef Full Text | Google Scholar

Sjøgren, P., Jensen, N. H., and Jensen, T. S. (1994). Disappearance of morphine-induced hyperalgesia after discontinuing or substituting morphine with other opioid agonists. Pain 59, 313–316. doi: 10.1016/0304-3959(94)90084-1

CrossRef Full Text | Google Scholar

Sliepen, S. H. J., Korioth, J., Christoph, T., Tzschentke, T. M., Diaz-delCastillo, M., Heegaard, A. M., et al. (2021). The nociceptin/orphanin FQ receptor system as a target to alleviate cancer-induced bone pain in rats: model validation and pharmacological evaluation. Br. J. Pharmacol. 178, 1995–2007. doi: 10.1111/BPH.14899

PubMed Abstract | CrossRef Full Text | Google Scholar

Smit, T., Rogers, A. H., Garey, L., Allan, N. P., Viana, A. G., and Zvolensky, M. J. (2020). Anxiety sensitivity and pain intensity independently predict opioid misuse and dependence in chronic pain patients. Psychiatry Res. 294:113523. doi: 10.1016/J.PSYCHRES.2020.113523

PubMed Abstract | CrossRef Full Text | Google Scholar

Soares, F. H. C., Kubota, G. T., Fernandes, A. M., Hojo, B., Couras, C., Costa, B. V., et al. (2021). Prevalence and characteristics of new-onset pain in COVID-19 survivours, a controlled study. Eur. J. Pain 25, 1342–1354. doi: 10.1002/EJP.1755

PubMed Abstract | CrossRef Full Text | Google Scholar

Solecki, W., Ziolkowska, B., Krowka, T., Gieryk, A., Filip, M., and Przewlocki, R. (2009). Alterations of prodynorphin gene expression in the rat mesocorticolimbic system during heroin self-administration. Brain Res. 1255, 113–121. doi: 10.1016/J.BRAINRES.2008.12.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Spahn, V., del Vecchio, G., Labuz, D., Rodriguez-Gaztelumendi, A., Massaly, N., Temp, J., et al. (2017). A nontoxic pain killer designed by modeling of pathological receptor conformations. Science 355, 966–969. doi: 10.1126/SCIENCE.AAI8636

PubMed Abstract | CrossRef Full Text | Google Scholar

Spanagel, R., Herz, A., and Shippenberg, T. S. (1992). Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. Proc. Natl. Acad. Sci. U.S.A. 89, 2046–2050. doi: 10.1073/PNAS.89.6.2046

PubMed Abstract | CrossRef Full Text | Google Scholar

Spetea, M., van Rijn, R. M., Daibani, A., and Che, T. (2022). Spotlight on nociceptin/orphanin FQ receptor in the treatment of pain. Molecules 27:595. doi: 10.3390/MOLECULES27030595

PubMed Abstract | CrossRef Full Text | Google Scholar

Stein, B. D., Sherry, T. B., O’Neill, B., Taylor, E. A., and Sorbero, M. (2021). Rapid discontinuation of chronic, high-dose opioid treatment for pain: prevalence and associated factors. J. Gen. Intern. Med. 37, 1603–1609. doi: 10.1007/S11606-021-07119-3/TABLES/2

CrossRef Full Text | Google Scholar

Stein, C. (2013). Opioids, sensory systems and chronic pain. Eur. J. Pharmacol. 716, 179–187. doi: 10.1016/J.EJPHAR.2013.01.076

PubMed Abstract | CrossRef Full Text | Google Scholar

Stein, C. (2016). Opioid receptors. Annu. Rev. Med. 67, 433–451. doi: 10.1146/ANNUREV-MED-062613-093100

PubMed Abstract | CrossRef Full Text | Google Scholar

Stein, C., Clark, J. D., Oh, U., Vasko, M. R., Wilcox, G. L., Overland, A. C., et al. (2009). Peripheral mechanisms of pain and analgesia. Brain Res. Rev. 60, 90–113. doi: 10.1016/j.brainresrev.2008.12.017

PubMed Abstract | CrossRef Full Text | Google Scholar

Stein, C., Schäfer, M., and Machelska, H. (2003). Attacking pain at its source: new perspectives on opioids. Nat. Med. 9, 1003–1008. doi: 10.1038/nm908

PubMed Abstract | CrossRef Full Text | Google Scholar

Stevenson, G. W., Folk, J. E., Rice, K. C., and Negus, S. S. (2005). Interactions between δ and μ opioid agonists in assays of schedule-controlled responding, thermal nociception, drug self-administration, and drug versus food choice in rhesus monkeys: studies with SNC80 [(+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl) -3-methoxybenzyl]-N,N-diethylbenzamide] and heroin. J. Pharmacol. Exp. Ther. 314, 221–231. doi: 10.1124/jpet.104.082685

PubMed Abstract | CrossRef Full Text | Google Scholar

Stoeber, M., Jullié, D., Lobingier, B. T., Laeremans, T., Steyaert, J., Schiller, P. W., et al. (2018). A genetically encoded biosensor reveals location bias of opioid drug action. Neuron 98, 963.e5–976.e5. doi: 10.1016/j.neuron.2018.04.021

PubMed Abstract | CrossRef Full Text | Google Scholar

Sturgeon, J. A., Sullivan, M. D., Parker-Shames, S., Tauben, D., and Coelho, P. (2020). Outcomes in long-term opioid tapering and buprenorphine transition: a retrospective clinical data analysis. Pain Med. 21, 3635–3644. doi: 10.1093/pm/pnaa029

PubMed Abstract | CrossRef Full Text | Google Scholar

Taylor, A. M. W., Castonguay, A., Taylor, A. J., Murphy, N. P., Ghogha, A., Cook, C., et al. (2015). Microglia disrupt mesolimbic reward circuitry in chronic pain. J. Neurosci. 35:8442. doi: 10.1523/JNEUROSCI.4036-14.2015

PubMed Abstract | CrossRef Full Text | Google Scholar

Taylor, A. M. W. W., Becker, S., Schweinhardt, P., and Cahill, C. (2016). Mesolimbic dopamine signaling in acute and chronic pain: implications for motivation, analgesia, and addiction. Pain 157:1194. doi: 10.1097/j.pain.0000000000000494

PubMed Abstract | CrossRef Full Text | Google Scholar

Tejeda, H. A., and Bonci, A. (2019). Dynorphin/kappa-opioid receptor control of dopamine dynamics: implications for negative affective states and psychiatric disorders. Brain Res. 1713, 91–101. doi: 10.1016/J.BRAINRES.2018.09.023

PubMed Abstract | CrossRef Full Text | Google Scholar

Tejeda, H. A., Counotte, D. S., Oh, E., Ramamoorthy, S., Chefer, V., Donnell, P. O., et al. (2013). Prefrontal cortical kappa-opioid receptor modulation of local neurotransmission and conditioned place aversion. Neuropsychopharmacology 38, 1770–1779. doi: 10.1038/npp.2013.76

PubMed Abstract | CrossRef Full Text | Google Scholar

Tejeda, H. A., Wu, J., Kornspun, A. R., Pignatelli, M., Kashtelyan, V., Krashes, M. J., et al. (2017). Pathway- and cell-specific kappa-opioid receptor modulation of excitation-inhibition balance differentially gates D1 and D2 accumbens neuron activity. Neuron 93, 147–163. doi: 10.1016/j.neuron.2016.12.005

PubMed Abstract | CrossRef Full Text | Google Scholar

Terenius, L. (1973). Stereospecific interaction between narcotic analgesics and a synaptic plasma membrane fraction of rat cerebral cortex. Acta Pharmacol. Toxicol. 32, 317–320. doi: 10.1111/j.1600-0773.1973.tb01477.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Thompson, S. J., Pitcher, M. H., Stone, L. S., Tarum, F., Niu, G., Chen, X., et al. (2018). Chronic neuropathic pain reduces opioid receptor availability with associated anhedonia in rat. Pain 159, 1856–1866. doi: 10.1097/J.PAIN.0000000000001282

PubMed Abstract | CrossRef Full Text | Google Scholar

Toll, L., Bruchas, M. R., Calo’, G., Cox, B. M., and Zaveri, N. T. (2016). Nociceptin/Orphanin FQ receptor structure, signaling, ligands, functions, and interactions with opioid systems. Pharmacol. Rev. 68, 419–457. doi: 10.1124/PR.114.009209

PubMed Abstract | CrossRef Full Text | Google Scholar

Torregrossa, M. M., Jutkiewicz, E. M., Mosberg, H. I., Balboni, G., Watson, S. J., and Woods, J. H. (2006). Peptidic delta opioid receptor agonists produce antidepressant-like effects in the forced swim test and regulate BDNF mRNA expression in rats. Brain Res. 1069, 172–181. doi: 10.1016/j.brainres.2005.11.005

PubMed Abstract | CrossRef Full Text | Google Scholar

Toubia, T., and Khalife, T. (2019). The endogenous opioid system: role and dysfunction caused by opioid therapy. Clin. Obstet. Gynecol. 62, 3–10. doi: 10.1097/GRF.0000000000000409

PubMed Abstract | CrossRef Full Text | Google Scholar

Tremblay, J., and Hamet, P. (2010). Genetics of pain, opioids, and opioid responsiveness. Metabolism 59, S5–S8. doi: 10.1016/J.METABOL.2010.07.015

PubMed Abstract | CrossRef Full Text | Google Scholar

Trujillo, K. A., Bronstein, D. M., Sanchez, I. O., and Akil, H. (1995). Effects of chronic opiate and opioid antagonist treatment on striatal opioid peptides. Brain Res. 698, 69–78. doi: 10.1016/0006-8993(95)00809-5

CrossRef Full Text | Google Scholar

Truong, W., Cheng, C., Xu, Q. G., Li, X. Q., and Zochodne, D. W. (2003). μ Opioid receptors and analgesia at the site of a peripheral nerve injury. Ann. Neurol. 53, 366–375. doi: 10.1002/ana.10465

PubMed Abstract | CrossRef Full Text | Google Scholar

Tzschentke, T. M., Linz, K., Frosch, S., and Christoph, T. (2017). Antihyperalgesic, antiallodynic, and antinociceptive effects of cebranopadol, a novel potent nociceptin/orphanin FQ and opioid receptor agonist, after peripheral and central administration in rodent models of neuropathic pain. Pain Pract. 17, 1032–1041. doi: 10.1111/papr.12558

PubMed Abstract | CrossRef Full Text | Google Scholar

Tzschentke, T. M., Linz, K., Koch, T., and Christoph, T. (2019). Cebranopadol: a novel first-in-class potent analgesic acting via NOP and opioid receptors. Handb. Exp. Pharmacol. 254, 367–398. doi: 10.1007/164_2019_206

CrossRef Full Text | Google Scholar

U.S. Department of Health and Human Services (2019). Pain Management Best Practices Inter-Agency Task Force Report: Updates, Gaps, Inconsistencies, and Recommendations. Washington, DC: U.S. Department of Health and Human Services.

Google Scholar

Ueda, H., Yamaguchi, T., Tokuyama, S., Inoue, M., Nishi, M., and Takeshima, H. (1997). Partial loss of tolerance liability to morphine analgesia in mice lacking the nociceptin receptor gene. Neurosci. Lett. 237, 136–138. doi: 10.1016/S0304-3940(97)00832-X

CrossRef Full Text | Google Scholar

Ur, E., Wright, D. M., Bouloux, P. M. G., and Grossman, A. (1997). The effects of spiradoline (U-62066E), a kappa-opioid receptor agonist, on neuroendocrine function in man. Br. J. Pharmacol. 120, 781–784. doi: 10.1038/SJ.BJP.0700971

PubMed Abstract | CrossRef Full Text | Google Scholar

Valentino, R. J., and Volkow, N. D. (2018). Untangling the complexity of opioid receptor function. Neuropsychopharmacology 43, 2514–2520. doi: 10.1038/s41386-018-0225-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Vanderah, T. W., Suenaga, N. M. H., Ossipov, M. H., Malan, J., Lai, J., and Porreca, F. (2001). Tonic descending facilitation from the rostral ventromedial medulla mediates opioid-induced abnormal pain and antinociceptive tolerance. J. Neurosci. 21, 279–286. doi: 10.1523/jneurosci.21-01-00279.2001

PubMed Abstract | CrossRef Full Text | Google Scholar

Vergara, F., Sardi, N. F., Pescador, A. C., Guaita, G. O., Jark Stern, C. A., Chichorro, J. G., et al. (2020). Contribution of mesolimbic dopamine and kappa opioid systems to the transition from acute to chronic pain. Neuropharmacology 178:108226. doi: 10.1016/J.NEUROPHARM.2020.108226

PubMed Abstract | CrossRef Full Text | Google Scholar

Viana, M. C., Lim, C. C. W., Garcia Pereira, F., Aguilar-Gaxiola, S., Alonso, J., Bruffaerts, R., et al. (2018). Previous mental disorders and subsequent onset of chronic back or neck pain: findings from 19 countries. J. Pain 19, 99–110. doi: 10.1016/J.JPAIN.2017.08.011

PubMed Abstract | CrossRef Full Text | Google Scholar

Volkow, N., Benveniste, H., and McLellan, A. T. (2018). Use and misuse of opioids in chronic pain. Annu. Rev. Med. 69, 451–465. doi: 10.1146/ANNUREV-MED-011817-044739

PubMed Abstract | CrossRef Full Text | Google Scholar

Volkow, N. D., and McLellan, A. T. (2016). Opioid abuse in chronic pain — misconceptions and mitigation strategies. New Engl. J. Med. 374, 1253–1263. doi: 10.1056/NEJMRA1507771

PubMed Abstract | CrossRef Full Text | Google Scholar

Vollstädt-Klein, S., Bumb, J. M., Otto, A., Dinter, C., Karl, D., Koopmann, A., et al. (2019). The effects of nalmefene on emotion processing in alcohol use disorder - A randomized, controlled fMRI study. Eur. Neuropsychopharmacol. 29, 1442–1452. doi: 10.1016/J.EURONEURO.2019.10.014

PubMed Abstract | CrossRef Full Text | Google Scholar

Voon, P., Karamouzian, M., and Kerr, T. (2017). Chronic pain and opioid misuse: a review of reviews. Subst. Abuse Treat. Prev. Policy 12, 1–9. doi: 10.1186/S13011-017-0120-7/TABLES/3

PubMed Abstract | CrossRef Full Text | Google Scholar

Vowles, K. E., McEntee, M. L., Julnes, P. S., Frohe, T., Ney, J. P., and van der Goes, D. N. (2015). Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. Pain 156, 569–576. doi: 10.1097/01.j.pain.0000460357.01998.f1

CrossRef Full Text | Google Scholar

Wade, C. L., Krumenacher, P., Kitto, K. F., Peterson, C. D., Wilcox, G. L., and Fairbanks, C. A. (2013). Effect of chronic pain on fentanyl self-administration in mice. PLoS One 8:e79239. doi: 10.1371/journal.pone.0079239

PubMed Abstract | CrossRef Full Text | Google Scholar

Wakaizumi, K., Jabakhanji, R., Ihara, N., Kosugi, S., Terasawa, Y., Morisaki, H., et al. (2019). Altered functional connectivity associated with time discounting in chronic pain. Sci. Rep. 9:8154. doi: 10.1038/S41598-019-44497-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Walker, J. R., Spina, M., Terenius, L., and Koob, G. F. (1998). Nociceptin fails to affect heroin self-administration in the rat. Neuroreport 9, 2243–2247. doi: 10.1097/00001756-199807130-00017

PubMed Abstract | CrossRef Full Text | Google Scholar

Walsh, S. L., Preston, K. L., Stitzer, M. L., Cone, E. J., and Bigelow, G. E. (1994). Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin. Pharmacol. Ther. 55, 569–580. doi: 10.1038/clpt.1994.71

PubMed Abstract | CrossRef Full Text | Google Scholar

Wandner, L. D., Domenichiello, A. F., Beierlein, J., Pogorzala, L., Aquino, G., Siddons, A., et al. (2022). NIH’s helping to end addiction long-termSM initiative (NIH HEAL initiative) clinical pain management common data element program. J. Pain 23, 370–378. doi: 10.1016/J.JPAIN.2021.08.005

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, D., Tawfik, V. L., Corder, G., Low, S. A., François, A., Basbaum, A. I., et al. (2018). Functional divergence of Delta and Mu opioid receptor organization in CNS pain circuits. Neuron 98, 90.e5–108.e5. doi: 10.1016/J.NEURON.2018.03.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, H., Zhang, Y., Ma, X., Wang, W., Xu, X., Huang, M., et al. (2020). Spinal TLR4/P2X7 receptor-dependent NLRP3 inflammasome activation contributes to the development of tolerance to morphine-induced antinociception. J. Inflamm. Res. 13, 571–582. doi: 10.2147/JIR.S266995

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, H. Y., Friedman, E., Olmstead, M. C., and Burns, L. H. (2005). Ultra-low-dose naloxone suppresses opioid tolerance, dependence and associated changes in mu opioid receptor–G protein coupling and Gβγ signaling. Neuroscience 135, 247–261. doi: 10.1016/J.NEUROSCIENCE.2005.06.003

PubMed Abstract | CrossRef Full Text | Google Scholar

Ward, J., Hall, W., and Mattick, R. (2009). “Methadone maintenance treatment,” in Pharmacotherapies for the Treatment of Opioid Dependence: Efficacy, Cost-Effectiveness, and Implementation Guidelines, eds R. P. Mattick, R. Ali, and N. Lintzeris (Boca Raton, FL: CRC Press), 107–141.

Google Scholar

Wardlaw, S. L., Kim, J., and Sobieszczyk, S. (1996). Effect of morphine on proopiomelanocortin gene expression and peptide levels in the hypothalamus. Brain Res. Mol. Brain Res. 41, 140–147. doi: 10.1016/0169-328X(96)00084-8

CrossRef Full Text | Google Scholar

Wawrzczak-Bargieła, A., Ziółkowska, B., Piotrowska, A., Starnowska-Sokół, J., Rojewska, E., Mika, J., et al. (2020). Neuropathic pain dysregulates gene expression of the forebrain opioid and dopamine systems. Neurotox Res. 37, 800–814. doi: 10.1007/S12640-020-00166-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Williams, J. T., Christie, M. J., and Manzoni, O. (2001). Cellular and synaptic adaptations mediating opioid dependence. Physiol. Rev. 81, 299–343. doi: 10.1152/PHYSREV.2001.81.1.299

PubMed Abstract | CrossRef Full Text | Google Scholar

Wilsey, B. L., Fishman, S. M., Tsodikov, A., Ogden, C., Symreng, I., and Ernst, A. (2008). Psychological comorbidities predicting prescription opioid abuse among patients in chronic pain presenting to the emergency department. Pain Med. 9, 1107–1117. doi: 10.1111/J.1526-4637.2007.00401.X

PubMed Abstract | CrossRef Full Text | Google Scholar

Witkin, J. M., Statnick, M. A., Rorick-Kehn, L. M., Pintar, J. E., Ansonoff, M., Chen, Y., et al. (2014). The biology of Nociceptin/Orphanin FQ (N/OFQ) related to obesity, stress, anxiety, mood, and drug dependence. Pharmacol. Ther. 141, 283–299. doi: 10.1016/J.PHARMTHERA.2013.10.011

PubMed Abstract | CrossRef Full Text | Google Scholar

Woller, S. A., Malik, J. S., Aceves, M., and Hook, M. A. (2014). Morphine Self-Administration following Spinal Cord Injury. J. Neurotrauma 31, 1570–1583.

Google Scholar

Worley, M. J., Heinzerling, K. G., Shoptaw, S., and Ling, W. (2015). Pain volatility and prescription opioid addiction treatment outcomes in patients with chronic pain. Exp. Clin. Psychopharmacol. 23, 428–435. doi: 10.1037/PHA0000039

PubMed Abstract | CrossRef Full Text | Google Scholar

Worley, M. J., Heinzerling, K. G., Shoptaw, S., and Ling, W. (2017). Volatility and change in chronic pain severity predict outcomes of treatment for prescription opioid addiction. Addiction 112, 1202–1209. doi: 10.1111/add.13782

PubMed Abstract | CrossRef Full Text | Google Scholar

Xu, M., Petraschka, M., McLaughlin, J. P., Westenbroek, R. E., Caron, M. G., Lefkowitz, R. J., et al. (2004). Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance. J. Neurosci. 24, 4576–4584. doi: 10.1523/JNEUROSCI.5552-03.2004

PubMed Abstract | CrossRef Full Text | Google Scholar

Xu, X. J., Hao, J. X., and Wiesenfeld-Hallin, Z. (1996). Nociceptin or antinociceptin: potent spinal antinociceptive effect of orphanin FQ/nociceptin in the rat. Neuroreport 7, 2092–2094.

Google Scholar

Yamamoto, T., Nozaki-Taguchi, N., and Kimura, S. (1997). Analgesic effect of intrathecally administered nociceptin, an opioid receptor-like receptor agonist, in the rat formalin test. Neuroscience 81, 249–254.

Google Scholar

Yasuda, K., Raynor, K., Kong, H., Breder, C., Takeda, J., Reisine, T., et al. (1993). Cloning and functional comparison of kappa and delta opioid receptors from mouse brain. Proc. Natl. Acad. Sci. U.S.A. 90, 6736–6740.

Google Scholar

Yovell, Y., Bar, G., Mashiah, M., Baruch, Y., Briskman, I., Asherov, J., et al. (2016). Ultra-low-dose buprenorphine as a time-limited treatment for severe suicidal ideation: a randomized controlled trial. Am. J. Psychiatry 173, 491–498. doi: 10.1176/APPI.AJP.2015.15040535

PubMed Abstract | CrossRef Full Text | Google Scholar

Zajacova, A., Grol-Prokopczyk, H., and Zimmer, Z. (2021). Pain trends among american adults, 2002–2018: patterns, disparities, and correlates. Demography 58, 711–738. doi: 10.1215/00703370-8977691

PubMed Abstract | CrossRef Full Text | Google Scholar

Zaveri, N. T., Marquez, P. V., Meyer, M. E., Hamid, A., and Lutfy, K. (2018). The nociceptin receptor (NOP) agonist AT-312 blocks acquisition of morphine- and cocaine-induced conditioned place preference in mice. Front. Psychiatry 9:638. doi: 10.3389/fpsyt.2018.00638

PubMed Abstract | CrossRef Full Text | Google Scholar

Zernig, G., Ahmed, S. H., Cardinal, R. N., Morgan, D., Acquas, E., Foltin, R. W., et al. (2007). Explaining the escalation of drug use in substance dependence: models and appropriate animal laboratory tests. Pharmacology 80, 65–119. doi: 10.1159/000103923

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, G., Lagrange, A. H., Rønnekleiv, O. K., and Kelly, M. J. (1996). Tolerance of hypothalamic β-endorphin neurons to μ-opioid receptor activation after chronic morphine. J. Pharmacol. Exp. Ther. 277, 551–558.

Google Scholar

Zhang, H., Kranzler, H. R., Yang, B. Z., Luo, X., and Gelernter, J. (2008). The OPRD1 and OPRK1 loci in alcohol or drug dependence: OPRD1 variation modulates substance dependence risk. Mol. Psychiatry 13, 531–543. doi: 10.1038/SJ.MP.4002035

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, X., Bao, L., Shi, T. J., Ju, G., Elde, R., and Hökfelt, T. (1998). Down-regulation of mu-opioid receptors in rat and monkey dorsal root ganglion neurons and spinal cord after peripheral axotomy. Neuroscience 82, 223–240. doi: 10.1016/S0306-4522(97)00240-6

CrossRef Full Text | Google Scholar

Zhang, X. Y., Dou, Y. N., Yuan, L., Li, Q., Zhu, Y. J., Wang, M., et al. (2020). Different neuronal populations mediate inflammatory pain analgesia by exogenous and endogenous opioids. eLife 9:e55289. doi: 10.7554/eLife.55289

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhou, J., Ma, R., Jin, Y., Fang, J., Du, J., Shao, X., et al. (2021). Molecular mechanisms of opioid tolerance: from opioid receptors to inflammatory mediators (Review). Exp. Ther. Med. 22, 1–8. doi: 10.3892/ETM.2021.10437

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhu, Y., King, M. A., Schuller, A. G. P., Nitsche, J. F., Reidl, M., Elde, R. P., et al. (1999). Retention of supraspinal delta-like analgesia and loss of morphine tolerance in delta opioid receptor knockout mice. Neuron 24, 243–252. doi: 10.1016/S0896-6273(00)80836-3

CrossRef Full Text | Google Scholar

Zöllner, C., and Stein, C. (2007). Opioids. Handb. Exp. Pharmacol. 177, 31–63. doi: 10.1007/978-3-540-33823-9_2

CrossRef Full Text | Google Scholar

Zubieta, J. K., Smith, Y. R., Bueller, J. A., Xu, Y., Kilbourn, M. R., Jewett, D. M., et al. (2001). Regional Mu opioid receptor regulation of sensory and affective dimensions of pain. Science 293, 311–315. doi: 10.1126/science.1060952

PubMed Abstract | CrossRef Full Text | Google Scholar

Zubieta, J. K., Smith, Y. R., Bueller, J. A., Xu, Y., Kilbourn, M. R., Jewett, D. M., et al. (2002). μ-opioid receptor-mediated antinociceptive responses differ in men and women. J. Neurosci. 22, 5100–5107. doi: 10.1523/jneurosci.22-12-05100.2002

PubMed Abstract | CrossRef Full Text | Google Scholar