Zili Yin1†
Xinlian Song
Rong Chen- 1Yunnan Key Laboratory of Dai and Yi Medicines, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
- 2Kunming Medical University Haiyuan College, Kunming, Yunnan, China
Chronic pain represents a significant global health concern, posing a severe threat to human wellbeing and affecting up to 20% of the adult population. Bulleyaconitine A (BLA), a diterpenoid alkaloid derived from plants of the Aconitum genus with in the Ranunculaceae family, demonstrates remarkable analgesic properties with a low potential for addiction, thus broad clinical application prospects compared to opioids. Extensive research has elucidated multiple pharmacological mechanisms underlying the analgesic effects of BLA, including state-dependent blockade of voltage-gated sodium channels, activation of the κ-opioid receptor pathway in spinal microglia, and anti-inflammatory immunomodulatory effects through inhibition of the NF-κB pathway. These mechanisms have been validated in various pain models, including neuropathic pain, cancer pain, rheumatoid arthritis pain, and visceral pain. However, BLA still faces pharmacokinetic challenges in clinical translation, including a narrow therapeutic window, low bioavailability, and potential neurotoxicity. In recent years, the development of novel drug delivery systems, structural modifications targeting the C-8 and C-14 sites to separate toxicity from efficacy, and advances in artificial intelligence-assisted drug design have provided effective solutions to overcome these limitations. Emerging research suggests that BLA has potential new indications in areas such as visceral hypersensitivity, irritable bowel syndrome, and pain-related anxiety disorders. This article provides a comprehensive review of the ion channel targets, central and peripheral mechanisms of action, pharmacokinetic characteristics, innovative drug delivery strategies, structural optimization pathways, and current clinical application of BLA. It aims to offer valuable references for the further development and rational clinical application of BLA as a non-opioid analgesic with multi-target therapeutic potential.
1 Introduction
Pain is defined as a physical or emotional discomfort associated with actual or potential tissue damage (Malik, 2020). Based on its characteristics, pain is categorized into chronic pain, neuropathic pain, and nociceptive pain (Kataria et al., 2024). Patients frequently experience severe sleep disturbances, anxiety, and depression, which significantly impair their quality of life (Rao et al., 2024). According to data from the World Health Organization (WHO), up to 20% of adults worldwide experience pain, highlighting its status as a significant public health concern (Kosek et al., 2016).
Currently, the commonly employed clinical methods for pain management encompass both pharmacological and non-pharmacological treatments. Pharmacological interventions include opioids and nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, while non-pharmacological approaches comprise cognitive behavioral therapy, physical therapy, and interventional procedures like nerve blocks (He et al., 2024). Nevertheless, existing therapies present several limitations, including the potential for drug abuse, addiction, gastrointestinal adverse reactions, and risks associated with invasive procedures (Kaye et al., 2020). The structural diversity inherent in natural products underpins their varied and unique biological activities. Consequently, in the pursuit of treatments with reduced side effects, there has been a growing emphasis on traditional herbal medicines and their constituent monomeric compounds.
BLA was first isolated from the Ranunculaceae plant Aconitum bulleyanum (Aconitum bulleyanum Diels) by Wang Fengpeng and Fang Qicheng (Wang, 1981) in 1981. It is a significant component of the Aconitum genus. BLA is a diterpenoid alkaloid that has been included in the Chinese Pharmacopoeia (2020 edition) due to its biosafety and has been approved for clinical application in China. For its extraction and purification, ethanol or methanol is typically employed as the primary solvent, often in conjunction with ultrasonic treatment to enhance extraction efficiency. The crude extract undergoes acid-base refinement: it is initially dissolved in dilute hydrochloric acid (0.5%–1%) to solubilize the alkaloid, followed by pH adjustment to 9-10 using ammonia water to precipitate the free base, which is subsequently extracted with chloroform. Purification is achieved through silica gel column chromatography employing a chloroform-methanol gradient elution system, and the final medicinal-grade pure product is obtained via ethanol recrystallization (Fu et al., 2024).
Clinically, BLA was formally incorporated into the Expert Consensus on Diagnosis and Treatment of Neuropathic Pain in 2013 (Xu and Yao, 2023), and is also referened in the latest Chinese Guidelines for the Assessment and Management of Neuropathic Pain (2024 edition) as well as the Chinese Guidelines for the Diagnosis and Treatment of Chronic Post-Traumatic Pain (2023 edition)(Jia et al., 2025). BLA has demonstrated excellent anti-inflammatory and immunomodulatory effects, acting on multiple sites of pain perception and exhibiting dual pharmacological actions of central and peripheral analgesia. It has shown good efficacy in treating various types of chronic pain, including cancer pain (Ling et al., 2007), neuropathic pain (Yang et al., 2013), and rheumatoid arthritis pain (Tang et al., 1986). Reports indicate that BLA, compared to opioids, is non-addictive, and has fewer gastrointestinal adverse effects than nonsteroidal anti-inflammatory drugs like aspirin (Xiao et al., 2021), with its analgesic effect being stronger than that of morphine and aspirin (Tang et al., 1986).
Despite the promising potential of BLA, several challenges remain in its clinical translation, including a narrow therapeutic window, low bioavailability, cardiovascular toxicity (such as palpitations and arrhythmias),and potential neurotoxicity, which limit its broader clinical application. In recent years, advancements in drug delivery systems, structural modifications, and artificial intelligence-assisted drug design have led to a renewed recognition of BLA’s potential.
This article will review the mechanism of action, pharmacokinetics, and drug delivery strategies of BLA, as well as progress in structural modifications and toxicity separation.
Additionally, it will discuss clinical applications and prospects for new indications, proposing future development directions based on the latest research to provide references for its further development and rational utilization (Figure 1).
Figure 1. Preparation process and pharmacological effects of BLA.
2 BLA from single target to multi-pathway regulation
2.1 Ion channel targets
Ion channels are pivotal targets of BLA in its analgesic mechanism, encompassing voltage-gated sodium channels (VGSCs), transient receptor potential channels (TRP), and calcium channels, among others. These channels are essential for peripheral nociception and central pain transmission. Numerous studies have demonstrated that BLA induces analgesia by modulating these channels, thereby providing significant insights into its molecular mechanism (Figure 2).
Figure 2. BLA: From single target to regulation of multiple pathways.
2.1.1 Sodium channel state-dependent mechanism
Voltage-gated sodium channels (Nav) are critical targets for the treatment of various neurological disorders (Catterall et al., 2020). They primarily exist in three functional states: resting, activated, and inactivated (Catterall, 2014). BLA preferentially binds to inactivated channels during high-frequency firing or sustained depolarization, demonstrating a state-dependent blockade with minimal impact on resting neurons (Wang et al., 2007).
Wang et al. (2008) demonstrated through patch-clamp studies that BLA exhibits minimal inhibition on Nav1.7 and Nav1.8 in the resting state, yet significantly enhances blockade in the inactivated state. Further research by Xie et al. (Xie et al., 2018a) revealed that the IC50 for the inactivated state of Nav1.7 (132.9 ± 25.5 pM) is approximately 946 times lower than that for the resting state (125.7 ± 18.6 nM). Additionally, the IC50 for the inactivated state of Nav1.3 (20.3 ± 3.4 pM) is approximately 49,000 times lower than that for the resting state (995.6 ± 139.1 nM).
This property enables BLA to specifically inhibit hyperactivated neurons in neuropathic pain (Cummins et al., 2007) while minimally impacting normal nerve conduction (Ruiz and Kraus, 2015), thereby optimizing the preservation of normal nerve conduction function.
Recently, Xiao et al. (2025) employed cryo-electron microscopy to elucidate the structure of the BLA-human Nav1.3 complex. Their findings revealed that the complex binds to the site-2 position of the central pore of the channel, stabilizing the open conformation of the DI–DII S6 helix while partially obstructing the ion channel. This dual effect elucidates the mechanism by which the complex promotes channel opening while simultaneously inhibiting ionic current. This structural study lays a crucial foundation for the development of novel Nav modulators characterized by enhanced selectivity and an expanded therapeutic window.
2.1.2 Regulatory effects on TRPV1
The transient receptor potential vanilloid type 1 (TRPV1) is a crucial ion channel in nociceptive neurons that plays a significant role in the perception of heat, acidity, and inflammatory factors (Tominaga and Caterina, 2004). In conditions of chronic inflammation and neuropathic pain, excessive activation of TRPV1 results in hyperalgesia and spontaneous pain (Cortright and Szallasi, 2009). Research has demonstrated (Wei et al., 2020) that BLA significantly inhibits both mRNA and protein expression of the TRPV1 receptor in spinal cord tissue, exhibiting a clear dose-dependent effect. Furthermore, BLA reduces the expression levels of pro-apoptotic factors such as Fas, Caspase-3, and Caspase-6, thereby exerting a neuroprotective effect. This indicates that BLA not only operates through the classical sodium channel mechanism but may also inhibit neuronal apoptosis by downregulating the sensitivity of both central and peripheral TRPV1 receptors, consequently alleviating neuropathic pain (Table 1).
Table 1. Ion channel targets of the BLA.
2.2 Central microglia and the κ-opioid receptor pathway
2.2.1 The mechanism of action of central microglia
The analgesic effect of BLA in the central nervous system is not solely dependent on ion channels; it also plays a unique role by modulating microglia in the spinal dorsal horn (Huang et al., 2016; Li et al., 2016). In the context of chronic pain pathology, microglia in the spinal dorsal horn facilitate inflammatory responses and neuronal sensitization, which in turn exacerbates the transmission of pain signals (Clark et al., 2013; Tsuda et al., 2003).
Traditional views suggest that microglial activation is a significant driving factor in the chronicity of pain. However, Huang et al. (2016) confirmed that BLA-specific stimulation induces spinal microglia to express the endogenous κ-opioid receptor (KOR) agonist dynorphin A (Dyn A) (Grace et al., 2014), which inhibits the release of excitatory neurotransmitters and enhances the activity of inhibitory neurons, thereby producing an analgesic effect (Ji et al., 2018). Unlike traditional anti-inflammatory drugs, BLA does not inhibit peripheral pro-inflammatory factors, demonstrating selective regulatory characteristics.
Li et al. (2017) further elucidated the molecular signaling mechanisms by which the BLA regulates dynorphin A expression in microglia. The study demonstrated that the BLA first activates protein kinase A (PKA), which subsequently activates p38 mitogen-activated protein kinase (MAPK). The activated p38 MAPK then phosphorylates cAMP response element-binding protein (CREB) at the Ser133 site, thereby promoting the transcription of the prodynorphin gene (PPE).
This unique molecular mechanism holds significant therapeutic implications. BLA selectively induces microglia to release endogenous dynorphin A by activating the PKA-p38 MAPK-CREB pathway, rather than suppressing pro-inflammatory responses. Compared to traditional strategies for inhibiting microglia, this approach of activating the endogenous analgesic system mitigates the risk of excessive immune suppression.
Dynorphin A, an endogenous κ-opioid receptor agonist, exerts potent analgesic effects at the spinal level. Compared to traditional μ-opioid drugs, BLA-dependent KOR-mediated analgesia offers the advantages of lower addiction potential and fewer side effects (Lonze and Ginty, 2002). This selective signal transduction mechanism paves the way for the development of novel analgesic drugs, particularly as replacements for or supplements to traditional opioids (Chavkin et al., 1982).
2.2.2 Cross-mechanisms of morphine tolerance
The analgesic effect of BLA through the κ-opioid receptor pathway exhibits a complex cross-regulatory phenomenon with the μ-opioid receptor mechanism of morphine at the molecular level. Research (Li et al., 2010) has demonstrated that in a morphine-tolerant rat model, κ-opioid receptors are upregulated in the spinal cord and locus coeruleus, while they are downregulated in the dorsal root ganglion. Studies on molecular mechanisms (Yamada et al., 2006) have revealed a functional interaction between the κ-opioid receptor and the μ-opioid receptor.
Preclinical studies have further confirmed the synergistic effects of the combined application of BLA and morphine. Huang et al. demonstrated in various animal models of pain that BLA significantly enhance the analgesic effect of morphine while completely preventing the development of morphine tolerance (Huang et al., 2017). In neuropathic pain models, BLA not only inhibits formaldehyde-induced tonic pain but also produces additive analgesic effects in conjunction with morphine.
These findings hold significant clinical implications. By activating various opioid receptor subtypes and unique microglial regulatory mechanisms, BLA presents a novel therapeutic strategy for overcoming morphine tolerance. Particularly within multimodal analgesic regimens, BLA may function as an effective adjuvant to morphine, enhancing analgesic efficacy while minimizing the adverse effects associated with single-drug therapy.
2.3 Anti-inflammatory-immunomodulatory integrated effect
BLA, a natural diterpenoid alkaloid, exhibits a unique integrated mode of anti-inflammatory and immunomodulatory actions. This dual regulatory mechanism offers a novel approach for treating inflammatory diseases.
In terms of anti-inflammatory mechanisms, BLA significantly modulates the expression of pro-inflammatory factors. In a mouse model of allergic asthma (Zhan et al., 2019), BLA treatment notably reduced key pro-inflammatory factors, including IL-4, TNF-α, and MCP-1, in the bronchoalveolar lavage fluid. These factors are crucial mediators of allergic inflammatory responses and play a central regulatory role in the pathogenesis of asthma. More importantly, BLA simultaneously inhibits the NF-κB signaling pathway, which is pivotal in immunity, inflammation, and cell proliferation (Liu et al., 2017). This mechanism is significantly important for controlling inflammatory responses.
At the level of immunomodulation, BLA exhibits significant bidirectional regulatory characteristics. Research has demonstrated (Liu et al., 2020) that BLA suppresses airway hyperresponsiveness, pulmonary inflammation, and airway remodeling by restoring the Th1/Th2 balance. In an animal model of allergic asthma (Zhan et al., 2019), BLA not only significantly reduced the levels of total serum IgE and IgG but also decreased the counts of eosinophils, lymphocytes, and macrophages in the bronchoalveolar lavage fluid.
The integrated anti-inflammatory and immunomodulatory effects of BLA hold significant pathophysiological implications. In the context of autoimmune diseases, the overactivation of the immune system results in the release of numerous pro-inflammatory factors and abnormal immune cell functions, leading to tissue damage and chronic inflammation (Song et al., 2024). BLA restores the inflammation-immune balance at the molecular level through a unique dual regulatory mechanism that simultaneously inhibits the production of pro-inflammatory factors and modulates the functional state of immune cells.
2.4 Bone repair and tissue microenvironment regulation (emerging research focus)
Bone repair is a complex biological process that involves the precise coordination of multiple stages, including inflammation regulation, angiogenesis, osteoblast differentiation, and modulation of osteoclast activity (Bahney et al., 2019). Maintaining a balance between osteoblasts and osteoclasts is crucial for effective bone healing (Mi et al., 2022). Recent studies have revealed that BLA exhibits a unique dual regulatory mechanism in promoting bone repair: it not only inhibits excessive osteoclast activity but also optimizes the local tissue microenvironment, thereby creating favorable conditions for the osteogenic process.
Peng et al. (2023) established a mouse model of tibial fracture to validate the promoting effect of BLA on bone repair. The results demonstrated that BLA not only effectively alleviated mechanical and thermal hyperalgesia induced by the fracture, but, more importantly, significantly promoted fracture healing.
In terms of cellular molecular mechanisms, the study by Zhang et al. elucidated the inhibitory effect of BLA on osteoclast differentiation (Zhang et al., 2018). The research demonstrated that BLA inhibits the activation of the NF-κB signaling pathway, thereby obstructing the formation of osteoclasts and the activity of bone resorption. Building upon this foundation, Wang et al. (2024) further illustrated that, in addition to regulating osteoclasts, BLA downregulates the expression of pro-inflammatory factors such as TNF-α, IL-1, and IL-6, while also diminishing the production of prostaglandin E2 (PGE2). This modulation of inflammatory microenvironment at the molecular level occurs during the early stages of fracture.
This multi-target regulatory mechanism holds significant clinical translational value. During the early inflammatory phase of fracture healing, excessive inflammatory responses can delay the healing process and exacerbate pain (ElHawary et al., 2021). BLA precisely regulates the release of inflammatory factors, maintaining the necessary inflammatory response to initiate the repair process while preventing excessive inflammation that could lead to tissue damage. Simultaneously, its selective inhibition of osteoclast activity ensures that bone formation predominates during remodeling. This characteristic endows BLA with broad application prospects in the treatment of orthopedic diseases. More importantly, the bone repair-promoting effect of BLA, coupled with its analgesic properties, offers a novel solution and research direction for addressing the clinical challenge posed by traditional analgesic drugs, such as non-steroidal anti-inflammatory drugs, which may interfere with bone healing (Al Farii et al., 2021) (Table 2).
Table 2. Multi-target mechanism of action of the BLA.
3 The pharmacokinetics of BLA
Although BLA demonstrates unique pharmacological advantages in its analgesic mechanism, it still encounters significant pharmacokinetic challenges in clinical applications, including complex drug metabolism processes, poor in vivo stability, and low bioavailability. These issues severely limit the expansion of its therapeutic window and the enhancement of clinical safety. Therefore, a comprehensive understanding of the pharmacokinetic characteristics of BLA is crucial for optimizing its clinical application.
3.1 CYP450 metabolic mechanism and drug interaction risks
The cytochrome P450 (CYP450) enzyme system constitutes the core regulatory network for drug metabolism within the body (Klein and Zanger, 2013). By catalyzing oxidation, reduction, and hydrolysis reactions of drugs, it directly influences the blood concentration levels of these substances, thereby affecting their therapeutic efficacy and potential toxic reactions (Miksys and Tyndale, 2009). Among the various subtypes of the CYP450 enzyme system, CYP3A4 assumes a predominant role (Guengerich, 2008). As a structurally complex diterpenoid alkaloid, the metabolic transformation of BLA in the body heavily relies on the catalytic function of the CYP450 enzyme system. Consequently, any factors that influence the activity of CYP450 enzymes, such as drug interactions or environmental factors, may significantly alter the pharmacokinetic characteristics of BLA, thereby impacting the safety and efficacy of its clinical application.
Li et al. (2022) identified that BLA serves as a sensitive substrate and competitive inhibitor of CYP3A4, which may significantly contribute to its clinical adverse reactions. The inhibition of CYP3A4 activity by BLA impacts the metabolic clearance of other drugs, thereby increasing the risk of drug accumulation and toxicity.
Therefore, a comprehensive understanding of the CYP450 metabolic characteristics of BLA and the potential risks of drug interactions, along with the establishment of a personalized medication monitoring system, is crucial for enhancing the safety and efficacy of its clinical application.
3.2 Pharmacokinetic deficiencies (narrow therapeutic window, first-pass effect, short half-life)
3.2.1 Narrow therapeutic window and safety challenges
The therapeutic window serves as a critical indicator for assessing drug safety (Bémeur et al., 2007). As an aconitum alkaloid, BLA demonstrates both cardiac and neurotoxic effects, and its therapeutic window is notably narrow. The cardiovascular toxicity of BLA primarily manifests as palpitations, arrhythmias—including ventricular tachycardia and atrial fibrillation—and, in severe cases, may lead to life-threatening cardiotoxicity characterized by hypotension and bradycardia (Wang et al., 2008; Wang et al., 2007). These cardiovascular adverse effects are dose-dependent and represent a significant safety concern that limits the clinical application of BLA. Similar to other aconitine-type alkaloids, BLA can induce cardiac arrhythmias by disrupting intracellular ion homeostasis, particularly affecting voltage-gated sodium and calcium channels (Sun et al., 2014). Therefore, electrocardiographic monitoring is essential during BLA administration, especially when higher doses or intravenous routes are employed (Li et al., 2022).
BLA has been utilized in China since 1985 for the management of chronic pain; however, the safety margin between its effective dose and toxic dose is relatively narrow (Wang et al., 2007). Safety evaluation studies (Yin et al., 2021), have demonstrated that BLA at a dosage of 0.14 mg/kg exhibits significant analgesic effects in both the hot plate test and the acetic acid writhing test. In subchronic toxicity studies, the no-observed-adverse-effect level (NOAEL) was identified as 0.25 mg/kg, while the lowest-observed-adverse-effect level (LOAEL) was determined to be 0.5 mg/kg.
The study conducted by Wang et al. (2007) further substantiates the characteristic of a narrow therapeutic window. In a rat model, a concentration of 0.125 mM BLA effectively provided cutaneous analgesia without significant systemic side effects. However, at an increased concentration of 0.25 mM, severe toxic symptoms manifested in the experimental animals. Furthermore, at a concentration of 0.5 mM, all experimental subjects (3/3) succumbed within the administration period (Wang et al., 2008).
This relatively narrow therapeutic window necessitates precise dosing control in clinical applications, as well as the establishment of an effective blood concentration monitoring system. Individual differences further complicate the therapeutic window issue. Due to the genetic diversity of CYP3A4 (Lamba et al., 2002), patients can exhibit several-fold differences in their response to the same dose of BLA (Ingelman-Sundberg, 2004). Individuals with fast metabolism may require higher doses to achieve effective blood concentrations, however, this correspondingly increases the risk of toxicity. Conversely, individuals with slow metabolism may experience drug accumulation and toxic reactions even at conventional doses (Burk and Wojnowski, 2004).
3.2.2 First-pass effect and bioavailability
BLA, a natural compound with multiple pharmacological activities, including anti-inflammatory effects, demonstrates promising potential in the treatment of rheumatoid arthritis. However, the significant first-pass effect encountered after oral administration severely limits the drug’s bioavailability and clinical efficacy.
To investigate the underlying causes of the low bioavailability of BLA, Li et al. elucidated the specific mechanisms involved in this process (Li et al., 2022). Research indicates that following gastrointestinal absorption, BLA is transported to the liver via the portal vein system, where it undergoes metabolism into various metabolites within hepatocytes. The analgesic activity of these metabolites is significantly lower than that of the parent compound, leading to a substantial reduction in therapeutic efficacy.
To overcome the limitations of the first-pass effect, researchers have explored various optimization strategies for drug delivery routes. Wang et al. (2007) demonstrated that subcutaneous administration of BLA effectively bypasses the hepatic first-pass effect, allowing the drug to reach effective concentrations directly at the site of action. Although intravenous administration can completely avoid the first-pass effect, it carries higher safety risks due to the cardiotoxicity associated with BLA. Therefore, clinical application necessitates strict electrocardiographic monitoring (Chan, 2009), which somewhat limits the feasibility of its clinical promotion.
3.2.3 Short half-life and dosing frequency issues
A short half-life represents another significant drawback in the pharmacokinetics of BLA. The plasma elimination half-life of BLA is relatively short (Weng et al., 2005), which hinders the drug’s ability to maintain a sustained effective concentration in the body. Consequently, a frequent dosing regimen is required to uphold therapeutic blood levels. This dosing strategy not only considerably increases the medication burden and treatment costs for patients but also elevates the risk of drug accumulation and cumulative toxic reactions.
The existence of these pharmacokinetic challenges underscores the importance of developing BLA drug formulation technologies. Innovations in drug formulation are expected to address the limitations of BLA regarding stability, bioavailability, and ease of administration, ultimately offering a safer and more effective analgesic treatment option for clinical practice.
4 Novel drug delivery system
In recent years, researchers have developed various novel drug delivery systems that have improved the pharmacokinetic properties of BLA. These advancements have resulted in a prolonged duration of action, enhanced bioavailability, and reduced toxic side effects, thereby offering new possibilities for precise treatment.
4.1 Sustained-release microsphere formulation
The microsphere drug delivery system exhibits significant potential for the local sustained-release administration of BLA. Wang et al. (2024) developed long-acting BLA microspheres (BLA-MS) for intra-articular injection, successfully controlling the initial burst release to an exceptionally low level. This characteristic of low burst release effectively mitigates toxic side effects caused by high local concentrations and significantly extends the drug’s retention time within the joint cavity.
In the collagen-induced arthritis rat model, the localized sustained-release system of BLA-MS establishes a drug reservoir at the lesion site. This approach mitigates the risks of inflammatory damage and infection associated with frequent dosing, thereby significantly enhancing patient compliance.
4.2 Liposome drug delivery system
Liposomes are biocompatible nanocarriers that exhibit excellent properties, including the ability to prolong drug action time through sustained-release mechanisms and to reduce toxic reactions (Allen and Cullis, 2013). More importantly, liposomal technology can facilitate targeted delivery via surface modification, thereby expanding the clinical application possibilities of BLA (Sercombe et al., 2015).
The long-acting local anesthetic bupivacaine (Exparel) provides analgesic effects lasting up to 96 h through the use of liposome technology (Hussain et al., 2021). Consequently, BLA is anticipated to enhance efficacy and improve safety through the application of this technology.
4.3 ROS-responsive targeted delivery system
The application of nanocarrier technology has demonstrated revolutionary advantages in enhancing the targeting and bioavailability of BLA. Smart nanocarriers facilitate the selective enrichment of drugs at the lesion site while simultaneously minimizing toxic side effects on normal tissues (Mitchell et al., 2021). Li et al. (2025) developed reactive oxygen species (ROS)-responsive hierarchical targeting micelles (TK-FA-BLA-MS), which construct dual-responsive smart nanocarriers by integrating ROS-sensitive thioketal (TK) units and M1 macrophage-specific targeting groups, such as folic acid (FA).
The immunomodulatory effect achieved through the regulation of macrophage phenotypes unveils a novel mechanism of action for BLA in the treatment of rheumatoid arthritis, transcending its traditional analgesic and anti-inflammatory functions. This effect enhances the uptake efficiency of activated macrophages and promotes their polarization, thereby establishing a groundbreaking mechanism of action for BLA in the management of rheumatoid arthritis (Zhang et al., 2017).
5 Exploration of structural modification and toxicity separation
The narrow therapeutic window of BLA has significantly restricted its clinical application. In recent years, advancements in our understanding of BLA’s molecular mechanisms, coupled with rapid progress in structural biology (Jiang et al., 2022), computational chemistry (Tonoyan and Siraki, 2024), and artificial intelligence technologies (Zhang et al., 2025), have facilitated the transition of the concept of “toxicity-efficacy separation” from a theoretical idea to a practical approach.
Structural modifications focus on selectively altering structural fragments that are closely related to toxicity but contribute relatively little to efficacy. Research has shown that while both the analgesic effect and neurotoxicity of BLA arise from its modulation of voltage-gated sodium channels, there are subtle differences in aspects such as binding sites. This provides a theoretical basis for achieving a separation of toxicity and efficacy through structural modifications. The philosophy of modern drug design aims to maintain or enhance analgesic activity while minimizing toxic side effects, employing systematic structure-activity relationship studies, innovative synthesis strategies, and intelligent molecular design (Guha, 2013) (Figure 3).
Figure 3. Key pharmacological and toxicological structural sites of BLA.
5.1 The relationship between essential groups and neurotoxicity
As a C19-type diterpenoid alkaloid, the acetyl ester group at the C-8 position and the benzoyl group at the C-14 position in the molecular structure of BLA are crucial for its pharmacological activity and toxicity. Structure-activity relationship studies (Ameri, 1998) have demonstrated that the ester substitutions at the C-8 and C-14 positions are the primary pharmacophores influencing its sodium ion channel binding activity. Modifications at these two sites directly impact the strength of the drug’s interaction with voltage-gated sodium ion channels (VGSCs), thereby determining the balance between its analgesic effects and neurotoxicity (Wang et al., 2010).
The presence of the C-8 acetyl ester group significantly enhances the compound’s affinity for sodium ion channels (Ameri, 1998), a structural feature that plays a dominant role in the toxic manifestations of aconitine-type alkaloids. Hydrolysis or substitution of the acetyl group at the C-8 position markedly reduces the acute toxicity of the compound; however, this alteration also weakens its analgesic activity (Li et al., 2016). In contrast, modifications to the C-14 benzoyl group exhibit a more complex influence on toxicity. Research indicates (Zhao et al., 2024) that the removal or substitution of the benzoyl group at the C-14 position can diminish neurotoxicity to some extent while preserving partial analgesic activity, thus providing a potential pathway for achieving a separation between toxicity and efficacy.
Moreover, a synergistic effect exists between the substituents at the C-8 and C-14 positions. When ester groups are present at both locations simultaneously, the compound demonstrates the strongest sodium channel blocking activity, albeit with a concomitant increase in toxicity risk (Bello-Ramírez and Nava-Ocampo, 2004). This discovery of the structure-activity-toxicity relationship has established a theoretical foundation for subsequent directed structural optimization (Table 3).
Table 3. Studies related to the synthesis of analogues and derivatives.
5.2 Advances in the synthesis of analogues and derivatives
In recent years, researchers have synthesized a series of BLA derivatives through structural modifications, aiming to reduce toxicity while maintaining or enhancing analgesic activity.
5.2.1 Nitrogen atom modification
Wang (2004) first conducted a systematic study on the chemical modification of the nitrogen atom in BLA by regulating the amount of NBS/HOAc used for this modification. The study revealed that utilizing 8 equivalents of NBS/HOAc at room temperature resulted in the formation of an imine compound with a yield of 73%. Furthermore, extending the reaction time led to the production of lactam products. Conversely, reducing the amount of NBS to 3 equivalents produced N-deethylated compounds with a yield of 90% (Figure 4).
Figure 4. Synthesis of target compounds 1-3.
The evaluation of analgesic activity demonstrated that the N-deethylated compound exhibited significantly greater analgesic efficacy (ED50 = 0.411 mg/kg) compared to the parent BLA, achieving an analgesic inhibition rate of 90% at a dosage of 0.80 mg/kg. In contrast, the imine compound (ED50 = 6.42 mg/kg) and the lactam compound (with an inhibition rate of 25.0% at 10 mg/kg) displayed markedly reduced analgesic activity. Furthermore, the structure-activity relationship analysis revealed that the nature of the substituent on the nitrogen atom of the A ring plays a crucial role in influencing the analgesic activity of these compounds.
5.2.2 C-8 position structural modification
5.2.2.1 Etherification reaction
Wang et al. (2009) developed a method for the C-8 modification of BLA by adapting the etherification conditions used for norditerpenoid alkaloids. Refluxing BLA in ethanol for 48 h resulted in the formation of the C-8 ethoxy compound, which was obtained with an impressive yield of 89%. This compound demonstrated significant analgesic activity, with an ED50 of 0.0972 mg/kg and an analgesic inhibition rate of 86.4% at a dose of 0.2 mg/kg (Figure 5).
Figure 5. Synthesis of target compounds 4.
Using isopentanol as the reaction medium, the reaction was conducted at 80 °C for 3 h, resulting in the formation of the C-8 isopentoxy derivative 6 with a yield of 30%. However, the analgesic inhibition rate of this compound was only 15.0% at a dosage of 10 mg/kg, suggesting that larger alkoxy substituents adversely affect the retention of activity (Mori et al., 1989) (Figure 6).
Figure 6. Synthesis of target compounds 5.
5.2.2.2 Esterification reaction
Lin and Song (2021) accomplished the esterification modification at the C-8 position via a multi-step synthesis. Initially, BLA was refluxed in a dioxane-water (1:1) mixed solvent to obtain the C-8 hydroxyl compound 6. This compound was subsequently esterified by reacting it with aryl acyl chloride in the presence of DMAP as a catalyst, using pyridine as the solvent and refluxing for 12 h, which yielded compound 7. The study revealed that both the solvent and temperature significantly influenced regioselectivity: refluxing in pyridine predominantly resulted in C-8/C-13 bis-esterified products, whereas the reaction conducted at room temperature in dichloromethane primarily yielded C-14 mono-esterified products (Figure 7).
Figure 7. Synthesis of target compounds 6-7.
5.2.3 C-14 position structural modification
5.2.3.1 Esterification reaction
Zhang et al. (2020) conducted the most comprehensive study to date on C-14 position modification. They began with the complete hydrolysis product obtained from the alkaline hydrolysis of BLA and reacted it with 27 different acyl chlorides in a pyridine/dichloromethane system at 40 °C for 2 h. This process resulted in the synthesis of a series of C-14 monoester derivatives, with yields ranging from 25% to 70%. The derivatives included aliphatic, aromatic, and heterocyclic carboxylate esters.
The hot plate analgesic test (10 mg/kg) revealed that six compounds exhibited remarkable analgesic activity, with pain threshold increases exceeding 100%. Notably, 5-chloro-2-thiophenecarboxylate demonstrated the most significant performance: at 15 min, the pain threshold increased by 166.35%, peaked at 182.35% at 30 min, and maintained a level of 82.59% at 60 min. This performance significantly surpassed that of BLA, which resulted in a pain threshold increase of only 69.60% at 60 min with a dosage of 0.35 mg/kg (Figure 8; Table 4).
Figure 8. Synthesis of target compounds 8.
Table 4. Synthesis of target compounds 8a-8w.
5.2.3.2 Amidobenzoate derivatives
Inspired by the modification of lappaconitine, Zhang et al. (2020) designed and synthesized a series of 2′-acylamino benzoates. The complete hydrolysis product reacted with phthalic anhydride in DMF at 120 °C for 7 h under DMAP catalysis, yielding the 2′-aminobenzoate intermediate with a yield of 63%. This intermediate was subsequently acylated to obtain five derivatives, with yields ranging from 30% to 59%. Although the analgesic activity of this series of compounds was slightly inferior to that of heterocyclic esters, it provided a structural basis for exploring the influence of hydrogen bonding on activity (Figure 9; Table 5).
Figure 9. Synthesis of target compound 9.
Table 5. Synthesis of target compounds 9a-9e.
5.2.3.3 Polyesterification research
To validate the assertion in the literature that “diester diterpenoid alkaloids exhibit stronger activity” (Cai et al., 2013), Zhang et al. reacted the optimal monoester compound (5-chloro-2-thiophenecarboxylate) with acryloyl chloride at 35 °C for 30 min, yielding the C-8 acetylated diester (35% yield) and the C-8/C-13 diacetylated triester (61% yield). Unexpectedly, the analgesic activity of the polyester compounds was significantly lower than that of the monoester parent, indicating that for BLA, monoester modification at the C-14 position is more conducive to maintaining activity (Figure 10; Table 6).
Figure 10. Synthesis of ester derivatives.
Table 6. Synthesis of target compounds 8w1-8w2.
5.2.3.4 Etherification reaction
The Wang group (Mori et al., 1989) reported an etherification modification at the C-14 position. The complete hydrolysis product was reacted with sodium hydride (NaH) in tetrahydrofuran (THF) for 2 h, followed by the slow addition of bromoethane and a continued reaction for 4 h. This process yielded the C-14 ethoxy mono-substituted and C-8/C-14 di-substituted products. This method offers an alternative strategy for constructing ether bonds; however, the activity data of the resulting products have not been fully reported (Figure 11).
Figure 11. Synthesis of target compounds 10-11.
Through systematic structural modifications at multiple sites of BLA, the researchers synthesized a series of novel derivatives that exhibit improved pharmacological properties. These compounds not only retained or enhanced the analgesic activity of the parent drug but also significantly reduced toxicity. Moreover, some compounds demonstrated additional therapeutic potentials, including anti-inflammatory and anxiolytic effects. Future research should continue to explore the structure-activity relationships to develop a new generation of safer and more effective analgesic drugs.
5.3 AI-assisted structure-activity relationship prediction
With the advancement of computational chemistry and artificial intelligence technologies, quantitative structure-activity relationship (QSAR) analysis, along with molecular docking techniques based on the BLA molecular structure, has provided theoretical guidance for research on the separation of toxicity and efficacy.
The BLA QSAR study has established a quantitative relationship between its structural characteristics and toxicity. Koleva et al. demonstrated that compounds possessing an aroyl/aroyloxy group at the C-14 position (such as BLA and aconitine) exhibit greater toxicity compared to those with an aroyloxy group at the C-4 position (Bello-Ramírez and Nava-Ocampo, 2004). Moreover, machine learning algorithms can develop QSAR models based on features such as molecular weight and partition coefficient, facilitating accurate predictions of BLA’s cardiac and neurotoxicity (Shah et al., 2024).
Furthermore, molecular docking technology can be employed to predict the binding modes and affinities of BLA and its derivatives with voltage-gated sodium ion channels. This approach enables the evaluation of the effects of C-8 acetyl ester and C-14 benzoyl modifications on the strength of protein-ligand binding.
By integrating various methods such as QSAR, molecular dynamics simulations, and free energy calculations (Turabekova et al., 2008), this study aims to provide systematic guidance for the separation of toxicity and efficacy in biological ligand activity (BLA) and to facilitate rational drug design.
5.4 Technology-driven BLA optimization
Biologics, as traditional natural products, face numerous challenges in modern clinical applications; however, technological innovations have opened broad prospects for their future development. Artificial intelligence is revolutionizing drug development models by employing machine learning algorithms to predict toxicity profiles and optimize compound structures, thereby providing new approaches for developing safer biologic derivatives (Fu and Chen, 2025). The intelligent design of novel drug delivery systems facilitates the precise development of targeted drug delivery and controlled-release formulations, which hold promise for addressing the bioavailability and targeting issues associated with biologics (Serrano et al., 2024).
The synergistic development of these technological innovations will facilitate the transformation of BLA from traditional analgesic drugs to individualized precision medicine, thereby playing a more significant role in the field of pain medicine.
6 Clinical translation and new indication prospects
With the in-depth development of modern pharmacological research, BLA has emerged as a significant drug in the field of pain management, exhibiting a unique non-opioid receptor-dependent analgesic mechanism. This characteristic enhances its potential for clinical application, particularly in light of the ongoing opioid abuse crisis.
6.1 Re-evaluation of efficacy in traditional indications (osteoarthritis, cancer pain, neuropathic pain, etc.)
BLA has received approval in China for the treatment of chronic pain and rheumatoid arthritis (Xie et al., 2018b). Recent clinical and basic research has further substantiated its traditional indications.
In the treatment of neuropathic pain, clinical studies have demonstrated that BLA can effectively alleviate human neuropathic pain (Wang et al., 2007). Furthermore, BLA has been shown to mitigate paclitaxel-induced neuropathic pain (Zhu et al., 2015).
In the treatment of arthritis, BLA demonstrates anti-inflammatory and analgesic effects by decreasing the expression of prostaglandin E2 (PGE2). Recent studies have developed long-acting BLA microspheres, which offer multidimensional therapy for rheumatoid arthritis via intra-articular administration, thereby showcasing their potential for localized drug delivery (Wang et al., 2024).
In the context of cancer pain, BLA has been shown to effectively inhibit both peripheral and central sensitization associated with chronic pain; however, it does not exert any influence on acute pain (Xie et al., 2018b).
In summary, BLA does not induce tolerance or addiction in the treatment of chronic pain. However, to further optimize its application in traditional indications, it is necessary to conduct more high-quality randomized controlled trials to verify its long-term efficacy and safety, as well as to establish standardized dosing regimens and monitoring indicators (Li et al., 2022).
6.2 The advantages of combination therapy with opioids
Current clinical guidelines for pain management increasingly emphasize the significance of multimodal analgesia. This approach minimizes adverse effects by employing medications with diverse mechanisms of action. A notable advantage of combining BLA in therapy is its capacity to diminish opioid tolerance. Research indicates (Mai et al., 2020) that BLA’s unique analgesic mechanism, which operates independently of opioid receptors, not only delivers effective pain relief but also mitigates opioid tolerance and dependence. This offers new avenues for developing safer and more effective pain management strategies (Zhu et al., 2015) (Table 7).
Table 7. Comparison of key pharmaceutical and clinical characteristics between BLA and morphine.
6.3 New potential areas
6.3.1 Visceral pain, IBS
Visceral pain is the primary symptom of irritable bowel syndrome (IBS), affecting approximately 10%–20% of the global population. The efficacy of traditional pharmacological therapies for IBS-related visceral pain is often suboptimal, underscoring the necessity for exploring new therapeutic targets and medications. BLA has demonstrated significant efficacy in treating chronic visceral hypersensitivity. In models of visceral pain induced by colonic inflammation, BLA effectively alleviates visceral pain responses and significantly improves visceral hypersensitivity (Huang et al., 2020a). Moreover, BLA is less likely to induce tolerance and addiction when alleviating visceral pain, thus providing a safer option for the long-term management of IBS-related visceral pain.
6.3.2 Adjuvant therapy for neuropsychiatric disorders (anti-anxiety)
Chronic pain frequently coexists with psychiatric symptoms, including anxiety and depression, which significantly diminish patients’ quality of life. Preclinical studies have demonstrated that BLA exhibits dual efficacy in the treatment of pain and anxiety. In animal models of chronic visceral hypersensitivity and comorbid anxiety (Huang et al., 2020b), BLA was shown to alleviate pain while simultaneously improving anxiety-like behaviors. Compared to traditional combination therapy approaches, BLA offers both analgesic and anxiolytic effects, which may enhance patient compliance (Li et al., 2025).
7 Conclusion
Chronic pain is a significant global health issue that necessitates the urgent development of safe and effective treatment options (Gregory et al., 2013; Xie et al., 2018b). Current treatment methods are limited by issues such as addiction and gastrointestinal adverse reactions (Baron et al., 2010). BLA, a diterpenoid alkaloid derived from plants in the genus Aconitum of the Ranunculaceae family, exerts analgesic effects through multiple mechanisms. These include a state-dependent blockade of voltage-gated sodium channels, activation of the κ-opioid receptor pathway in spinal microglia, anti-inflammatory and immunomodulatory actions, and promotion of bone repair. BLA demonstrates low addiction potential and minimal adverse reactions (Tang et al., 1986), and has shown significant efficacy in various pain models, including neuropathic pain, cancer pain, and rheumatoid arthritis.
However, the clinical translation of BLA still faces significant challenges. Its narrow therapeutic window, low bioavailability, risk of drug interactions, and potential neurotoxicity limit its widespread application (Weng et al., 2005). To address these limitations, researchers have made groundbreaking progress in various directions in recent years. Novel drug delivery systems have significantly improved the pharmacokinetic characteristics of BLA, extending its duration of action and minimizing adverse effects. Structural modification studies have successfully synthesized a series of BLA derivatives that separate toxicity from efficacy. Additionally, QSAR analysis and molecular docking techniques have provided robust tools for the rational design of BLA, thereby accelerating the translation process from the laboratory to clinical settings.
In clinical applications, BLA has demonstrated not only good efficacy in traditional indications but also significant therapeutic potential in emerging fields such as visceral hypersensitivity, irritable bowel syndrome, and pain-related anxiety disorders. Notably, when combined with opioids, BLA significantly enhances analgesic effects and completely inhibits the development of morphine tolerance, thereby providing a novel therapeutic strategy for multimodal analgesia.
In summary, BLA, a non-opioid analgesic with multi-target therapeutic potential, presents significant prospects for application in the field of pain medicine (Xie et al., 2018b). Future research should capitalize on these technological advancements to develop novel drugs that exhibit higher selectivity and broader therapeutic windows (Li et al., 2017). Additionally, it is crucial to construct safer, more efficient, and precisely controllable intelligent drug delivery platforms. This approach will facilitate the transformation of BLA from a traditional analgesic into a personalized precision therapeutic agent, thereby laying a solid foundation for its further development and clinical application, and offering new directions for the treatment of chronic pain.
Author contributions
ZY: Writing - review and editing. XS: Writing – original draft. CZ: Writing - review and editing. AH: Writing - review and editing. RC: Writing - review and editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. Yunnan International Joint Laboratory of Chinese and Laos Traditional Medicine (202503AP140023). Key Research and Development Plan of Yunnan Province Science andTechnology Department Social Development Special Plan (202403AC100017). Yunnan Province Joint Special Fund for Basic Research in Traditional Chinese Medicine (202101AZ070001-322, 202301AZ070001-034). The Open Project of Yunnan Key Laboratory of Dai and Yi Medicines (2024ZD2406).
Acknowledgements
The authors gratefully acknowledge the support of the Yunnan Province Dai and Yi Medicine Key Laboratory.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
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
Al Farii, H., Farahdel, L., Frazer, A., Salimi, A., and Bernstein, M. (2021). The effect of NSAIDs on postfracture bone healing: a meta-analysis of randomized controlled trials. OTA Int. 4 (2), e092. doi:10.1097/oi9.0000000000000092
Allen, T. M., and Cullis, P. R. (2013). Liposomal drug delivery systems: from concept to clinical applications. Adv. Drug Delivery Reviews 65 (1), 36–48. doi:10.1016/j.addr.2012.09.037
Ameri, A. (1998). The effects of aconitum alkaloids on the central nervous system. Prog. Neurobiology 56 (2), 211–235. doi:10.1016/S0301-0082(98)00037-9
Bahney, C. S., Zondervan, R. L., Allison, P., Theologis, A., Ashley, J. W., Ahn, J., et al. (2019). Cellular biology of fracture healing. J. Orthop. Res. 37 (1), 35–50. doi:10.1002/jor.24170
Baron, R., Binder, A., and Wasner, G. (2010). Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol. 9 (8), 807–819. doi:10.1016/s1474-4422(10)70143-5
Bello-Ramírez, A. M., and Nava-Ocampo, A. A. (2004). A QSAR analysis of toxicity of aconitum alkaloids. Fundam. & Clinical Pharmacology 18 (6), 699–704. doi:10.1111/j.1472-8206.2004.00280.x
Bémeur, C., Ste-Marie, L., and Montgomery, J. (2007). Increased oxidative stress during hyperglycemic cerebral ischemia. Neurochem. Int. 50 (7), 890–904. doi:10.1016/j.neuint.2007.03.002
Benyamin, R., Trescot, A. M., Datta, S., Buenaventura, R., Adlaka, R., Sehgal, N., et al. (2008). Opioid complications and side effects. Pain Physician 11 (2 Suppl. l), S105–S120. doi:10.36076/ppj.2008/11/S105
Berkowitz, B. A. (1976). The relationship of pharmacokinetics to pharmacological activity: morphine, methadone and naloxone. Clin. Pharmacokinet. 1 (3), 219–230. doi:10.2165/00003088-197601030-00004
Burk, O., and Wojnowski, L. (2004). Cytochrome P450 3A and their regulation. Naunyn-Schmiedeberg's Archives Pharmacology 369 (1), 105–124. doi:10.1007/s00210-003-0815-3
Cai, C., Yang, C., Liang, J., and Liu, J. (2013). Advance in studies on structure-activity relationships of diterpenoid alkaloids in genus aconitum. Strait Pharma J. 25, 1–5.
Catterall, W. A. (2014). Sodium channels, inherited epilepsy, and antiepileptic drugs. Annu. Rev. Pharmacol. Toxicol. 54 (54), 317–338. doi:10.1146/annurev-pharmtox-011112-140232
Catterall, W. A., Lenaeus, M. J., and Gamal El-Din, T. M. (2020). Structure and pharmacology of voltage-gated sodium and calcium channels. Annu. Rev. Pharmacol. Toxicol. 60 (1), 133–154. doi:10.1146/annurev-pharmtox-010818-021757
Chan, T. Y. (2009). Aconite poisoning. Clin. Toxicology 47 (4), 279–285. doi:10.1080/15563650902904407
Chavkin, C., James, I. F., and Goldstein, A. (1982). Dynorphin is a specific endogenous ligand of the kappa opioid receptor. Science 215 (4531), 413–415. doi:10.1126/science.6120570
Clark, A. K., Old, E. A., and Malcangio, M. (2013). Neuropathic pain and cytokines: current perspectives. J. Pain Res. 6, 803–814. doi:10.2147/jpr.S53660
Collett, B. J. (1998). Opioid tolerance: the clinical perspective. Br. J. Anaesth. 81 (1), 58–68. doi:10.1093/bja/81.1.58
Cortright, D. N., and Szallasi, A. (2009). TRP channels and pain. Curr. Pharm. Des. 15 (15), 1736–1749. doi:10.2174/138161209788186308
Cummins, T. R., Sheets, P. L., and Waxman, S. G. (2007). The roles of sodium channels in nociception: implications for mechanisms of pain. Pain 131 (3), 243–257. doi:10.1016/j.pain.2007.07.026
Darcq, E., and Kieffer, B. L. (2018). Opioid receptors: drivers to addiction? Nat. Rev. Neurosci. 19 (8), 499–514. doi:10.1038/s41583-018-0028-x
Dowell, D., Haegerich, T. M., and Chou, R. (2016). CDC guideline for prescribing opioids for chronic pain - united States, 2016. MMWR Recomm. Rep. 65 (1), 1–49. doi:10.15585/mmwr.rr6501e1
ElHawary, H., Baradaran, A., Abi-Rafeh, J., Vorstenbosch, J., Xu, L., and Efanov, J. I. (2021). Bone healing and inflammation: principles of fracture and repair. Semin. Plast. Surg. 35 (3), 198–203. doi:10.1055/s-0041-1732334
Fu, B. B., Jiang, Y. H., Ren, J. J., and Liu, J. F. (2024). A recycling and utilization method for column chromatography eluent in bulleyaconitine A extraction process. Chinese Patent Application CN 202310624725.7. Beijing, China: China National Intellectual Property Administration.
Fu, C., and Chen, Q. (2025). The future of pharmaceuticals: artificial intelligence in drug discovery and development. J. Pharm. Analysis 15, 101248. doi:10.1016/j.jpha.2025.101248
Funahashi, M., Kohda, H., Shikata, I., and Kimura, H. (1988). Potentiation of lethality and increase in body temperature by combined use of d-methamphetamine and morphine in mice. Forensic Science International 37 (1), 19–26. doi:10.1016/0379-0738(88)90103-x
Grace, P. M., Hutchinson, M. R., Maier, S. F., and Watkins, L. R. (2014). Pathological pain and the neuroimmune interface. Nat. Rev. Immunol. 14 (4), 217–231. doi:10.1038/nri3621
Grant, G. J., Vermeulen, K., Zakowski, M. I., Stenner, M., Turndorf, H., and Langerman, L. (1994). Prolonged analgesia and decreased toxicity with liposomal morphine in a mouse model. Anesth. Analg. 79 (4), 706–709. doi:10.1213/00000539-199410000-00015
Gregory, N. S., Harris, A. L., Robinson, C. R., Dougherty, P. M., Fuchs, P. N., and Sluka, K. A. (2013). An overview of animal models of pain: disease models and outcome measures. J. Pain 14 (11), 1255–1269. doi:10.1016/j.jpain.2013.06.008
Guengerich, F. P. (2008). Cytochrome P450 and chemical toxicology. Chem. Res. Toxicol. 21 (1), 70–83. doi:10.1021/tx700079z
Guha, R. (2013). On exploring structure-activity relationships. Methods Mol. Biol. 993, 81–94. doi:10.1007/978-1-62703-342-8_6
Hasselström, J., and Säwe, J. (1993). Morphine pharmacokinetics and metabolism in humans. Enterohepatic cycling and relative contribution of metabolites to active opioid concentrations. Clin. Pharmacokinet. 24 (4), 344–354. doi:10.2165/00003088-199324040-00007
He, J., Tse, M. M. Y., and Kwok, T. T. O. (2024). The effectiveness, acceptability, and sustainability of non-pharmacological interventions for chronic pain management in older adults in mainland China: a systematic review. Geriatr. Nurs. 57, 123–131. doi:10.1016/j.gerinurse.2024.04.008
Huang, Q., Mao, X. F., Wu, H. Y., Li, T. F., Sun, M. L., Liu, H., et al. (2016). Bullatine A stimulates spinal microglial dynorphin A expression to produce anti-hypersensitivity in a variety of rat pain models. J. Neuroinflammation 13 (1), 214. doi:10.1186/s12974-016-0696-2
Huang, Q., Sun, M.-L., Chen, Y., Li, X.-Y., and Wang, Y.-X. (2017). Concurrent bullatine A enhances morphine antinociception and inhibits morphine antinociceptive tolerance by indirect activation of spinal κ-opioid receptors. J. Ethnopharmacol. 196, 151–159. doi:10.1016/j.jep.2016.12.027
Huang, S.-N., Wei, J., Huang, L.-T., Ju, P.-J., Chen, J., and Wang, Y.-X. (2020a). Bulleyaconitine A inhibits visceral nociception and spinal synaptic plasticity through stimulation of microglial release of dynorphin A. Neural Plast. 2020 (1), 1484087. doi:10.1155/2020/1484087
Huang, S.-N., Yang, B., Ma, L., Huang, L.-T., Ju, P.-J., Wei, J., et al. (2020b). Bulleyaconitine A exerts antianxiety and antivisceral hypersensitivity effects. Front. Pharmacol. 11, 328. doi:10.3389/fphar.2020.00328
Hussain, N., Brull, R., Sheehy, B., Essandoh, M. K., Stahl, D. L., Weaver, T. E., et al. (2021). Perineural liposomal bupivacaine is not superior to nonliposomal bupivacaine for peripheral nerve block analgesia. Anesthesiology 134 (2), 147–164. doi:10.1097/aln.0000000000003651
Ingelman-Sundberg, M. (2004). Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms. Naunyn-Schmiedeberg's Archives Pharmacology 369 (1), 89–104. doi:10.1007/s00210-003-0819-z
Ji, R. R., Nackley, A., Huh, Y., Terrando, N., and Maixner, W. (2018). Neuroinflammation and central sensitization in chronic and widespread pain. Anesthesiology 129 (2), 343–366. doi:10.1097/aln.0000000000002130
Jia, H., Yu, Z., Fu, B., Gong, Y., and Liu, J. (2025). The research status of bulleyaconitine A. Chin. J. Ethnomedicine Ethnopharmacy 34. doi:10.3969/j.issn.1007-8517.2025.12.zgmzmjyyzz202512016
Jiang, D., Zhang, J., and Xia, Z. (2022). Structural advances in voltage-gated sodium channels. Front. Pharmacol. 13, 908867. doi:10.3389/fphar.2022.908867
Kataria, S., Patel, U., Yabut, K., Patel, J., Patel, R., Patel, S., et al. (2024). Recent advances in management of neuropathic, nociceptive, and chronic pain: a narrative review with focus on nanomedicine, gene therapy, stem cell therapy, and newer therapeutic options. Curr. Pain Headache Rep. 28 (5), 321–333. doi:10.1007/s11916-024-01227-5
Kaye, A. D., Kandregula, S., Kosty, J., Sin, A., Guthikonda, B., Ghali, G. E., et al. (2020). Chronic pain and substance abuse disorders: preoperative assessment and optimization strategies. Best Pract. & Res. Clin. Anaesthesiol. 34 (2), 255–267. doi:10.1016/j.bpa.2020.04.014
Klein, K., and Zanger, U. M. (2013). Pharmacogenomics of cytochrome P450 3A4: recent progress toward the “Missing Heritability” problem. Front. Genet. 4, 12. doi:10.3389/fgene.2013.00012
Kosek, E., Cohen, M., Baron, R., Gebhart, G. F., Mico, J.-A., Rice, A. S. C., et al. (2016). Do we need a third mechanistic descriptor for chronic pain states? Pain 157 (7), 1382–1386. doi:10.1097/j.pain.0000000000000507
Lamba, J. K., Lin, Y. S., Schuetz, E. G., and Thummel, K. E. (2002). Genetic contribution to variable human CYP3A-mediated metabolism. Adv. Drug Delivery Reviews 54 (10), 1271–1294. doi:10.1016/s0169-409x(02)00066-2
Li, X. Y., Sun, L., He, J., Chen, Z. L., Zhou, F., Liu, X. Y., et al. (2010). The kappa-opioid receptor is upregulated in the spinal cord and locus ceruleus but downregulated in the dorsal root ganglia of morphine tolerant rats. Brain Res. 1326, 30–39. doi:10.1016/j.brainres.2010.02.070
Li, T. F., Gong, N., and Wang, Y. X. (2016). Ester hydrolysis differentially reduces aconitine-induced anti-hypersensitivity and acute neurotoxicity: involvement of spinal microglial dynorphin expression and implications for aconitum processing. Front. Pharmacol. 7, 367. doi:10.3389/fphar.2016.00367
Li, T. F., Wu, H. Y., Wang, Y. R., Li, X. Y., and Wang, Y. X. (2017). Molecular signaling underlying bulleyaconitine A (BAA)-induced microglial expression of prodynorphin. Sci. Rep. 7, 45056. doi:10.1038/srep45056
Li, X., Ou, X., Ni, J., Xu, Y., Zuo, H., Fu, Y., et al. (2022). Bulleyaconitine A is a sensitive substrate and competitive inhibitor of CYP3A4: one of the possible explanations for clinical adverse reactions. Toxicol. Appl. Pharmacol. 445, 116024. doi:10.1016/j.taap.2022.116024
Li, S., Yang, S., Li, T., Ma, D., Yu, Y., Liu, Y., et al. (2025). Modulation of macrophage polarization in rheumatoid arthritis therapy via targeted delivery of bulleyaconitine A. ACS Appl. Nano Mater. 8 (9), 4513–4529. doi:10.1021/acsanm.4c06849
Lin, Y., and Song, L. (2021). The research status of bulleyaconitine. Chin. J. Ethnomedicine Ethnopharmacy 30 (20), 5. doi:10.3969/j.issn.1007-8517.2021.20.zgmzmjyyzz202120014
Ling, X., Li Xing, L., Ge, A., Shan, Y., Jie, L., and Mansky, P. J. (2007). Chinese herbal medicine for cancer pain. Integr. Cancer Ther. 6 (3), 208–234. doi:10.1177/1534735407305705
Liu, T., Zhang, L., Joo, D., and Sun, S.-C. (2017). NF-κB signaling in inflammation. Signal Transduct. Target. Ther. 2 (1), 17023. doi:10.1038/sigtrans.2017.23
Liu, L., Wang, S., Xing, H., Sun, Y., Ding, J., and He, N. (2020). Bulleyaconitine A inhibits the lung inflammation and airway remodeling through restoring Th1/Th2 balance in asthmatic model mice. Biosci. Biotechnol. Biochem. 84 (7), 1409–1417. doi:10.1080/09168451.2020.1752140
Lonze, B. E., and Ginty, D. D. (2002). Function and regulation of CREB family transcription factors in the nervous system. Neuron 35 (4), 605–623. doi:10.1016/s0896-6273(02)00828-0
Mai, J.-Z., Liu, C., Huang, Z., Mai, C.-L., Zhou, X., Zhang, J., et al. (2020). Oral application of bulleyaconitine A attenuates morphine tolerance in neuropathic rats by inhibiting long-term potentiation at C-fiber synapses and protein kinase C gamma in spinal dorsal horn. Mol. Pain 16, 1744806920917242. doi:10.1177/1744806920917242
Malik, N. A. (2020). Revised definition of pain by ‘international association for the study of pain’: concepts, challenges and compromises, 24, doi:10.35975/apic.v24i5.1352
Mao, J. (2002). Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy. Pain 100 (3), 213–217. doi:10.1016/s0304-3959(02)00422-0
Mi, B., Chen, L., Xiong, Y., Yang, Y., Panayi, A. C., Xue, H., et al. (2022). Osteoblast/osteoclast and immune cocktail therapy of an exosome/drug delivery multifunctional hydrogel accelerates fracture repair. ACS Nano 16 (1), 771–782. doi:10.1021/acsnano.1c08284
Miksys, S., and Tyndale, R. F. (2009). Brain drug-metabolizing cytochrome P450 enzymes are active in vivo, demonstrated by mechanism-based enzyme inhibition. Neuropsychopharmacology 34 (3), 634–640. doi:10.1038/npp.2008.110
Mitchell, M. J., Billingsley, M. M., Haley, R. M., Wechsler, M. E., Peppas, N. A., and Langer, R. (2021). Engineering precision nanoparticles for drug delivery. Nat. Reviews Drug Discovery 20 (2), 101–124. doi:10.1038/s41573-020-0090-8
Mori, T., Ohsawa, T., and Murayama, M. (1989). Studies On Aconitum Species. VIII. Heterocycles. 29 (5),
Niemegeers, C. J., Schellekens, K. H., Van Bever, W. F., and Janssen, P. A. (1976). Sufentanil, a very potent and extremely safe intravenous morphine-like compound in mice, rats and dogs. Arzneimittelforschung 26 (8), 1551–1556.
Peng, J., Xiao, S., Xie, J., and Fu, W. (2023). Bulleyaconitine A reduces fracture-induced pain and promotes fracture healing in mice. Front. Pharmacol. 14, 1046514. doi:10.3389/fphar.2023.1046514
Rao, Y., Li, J., Qiao, R., Luo, J., and Liu, Y. (2024). Synergistic effects of tetramethylpyrazine and astragaloside IV on spinal cord injury via alteration of astrocyte A1/A2 polarization through the Sirt1-NF-κB pathway. Int. Immunopharmacol. 131, 111686. doi:10.1016/j.intimp.2024.111686
Ruiz, M. D., and Kraus, R. L. (2015). Voltage-gated sodium channels: structure, function, pharmacology, and clinical indications. J. Med. Chem. 58 (18), 7093–7118. doi:10.1021/jm501981g
Sercombe, L., Veerati, T., Moheimani, F., Wu, S. Y., Sood, A. K., and Hua, S. (2015). Advances and challenges of liposome assisted drug delivery. Front. Pharmacol. 6, 286. doi:10.3389/fphar.2015.00286
Serrano, D. R., Luciano, F. C., Anaya, B. J., Ongoren, B., Kara, A., Molina, G., et al. (2024). Artificial intelligence (AI) applications in drug discovery and drug delivery: revolutionizing personalized medicine. Pharmaceutics 16 (10), 1328. doi:10.3390/pharmaceutics16101328
Shah, M., Patel, M., Shah, M., Patel, M., and Prajapati, M. (2024). Computational transformation in drug discovery: a comprehensive study on molecular docking and quantitative structure activity relationship (QSAR). Intell. Pharm. 2 (5), 589–595. doi:10.1016/j.ipha.2024.03.001
Song, Y., Li, J., and Wu, Y. (2024). Evolving understanding of autoimmune mechanisms and new therapeutic strategies of autoimmune disorders. Signal Transduct. Target. Ther. 9 (1), 263. doi:10.1038/s41392-024-01952-8
Sora, I., Elmer, G., Funada, M., Pieper, J., Li, X. F., Hall, F. S., et al. (2001). Mu opiate receptor gene dose effects on different morphine actions: evidence for differential in vivo mu receptor reserve. Neuropsychopharmacology 25 (1), 41–54. doi:10.1016/s0893-133x(00)00252-9
Stanski, D. R., Greenblatt, D. J., and Lowenstein, E. (1978). Kinetics of intravenous and intramuscular morphine. Clin. Pharmacol. Ther. 24 (1), 52–59. doi:10.1002/cpt197824152
Strandberg, J. J., Kugelberg, F. C., Alkass, K., Gustavsson, A., Zahlsen, K., Spigset, O., et al. (2006). Toxicological analysis in rats subjected to heroin and morphine overdose. Toxicol. Lett. 166 (1), 11–18. doi:10.1016/j.toxlet.2006.05.007
Sun, G. B., Sun, H., Meng, X. B., Hu, J., Zhang, Q., Liu, B., et al. (2014). Aconitine-induced Ca2+ overload causes arrhythmia and triggers apoptosis through p38 MAPK signaling pathway in rats. Toxicol. Appl. Pharmacol. 279 (1), 8–22. doi:10.1016/j.taap.2014.05.005
Tang, X., Liu, X., Lu, W., Wang, M. D., and Li, A. L. (1986). Studies on the analgesic action and physical dependence of bulleyaconitine A. Acta Pharm. Sin. 21 (12), 886–891. doi:10.16438/j.0513-4870.1986.12.002
Tominaga, M., and Caterina, M. J. (2004). Thermosensation and pain. J. Neurobiology 61 (1), 3–12. doi:10.1002/neu.20079
Tonoyan, L., and Siraki, A. G. (2024). Machine learning in toxicological sciences: opportunities for assessing drug toxicity. Front. Drug Discov. 4, 1336025. doi:10.3389/fddsv.2024.1336025
Tsuda, M., Shigemoto-Mogami, Y., Koizumi, S., Mizokoshi, A., Kohsaka, S., Salter, M. W., et al. (2003). P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424 (6950), 778–783. doi:10.1038/nature01786
Turabekova, M. A., Rasulev, B. F., Levkovich, M. G., Abdullaev, N. D., and Leszczynski, J. (2008). Aconitum and delphinium sp. alkaloids as antagonist modulators of voltage-gated Na+ channels: AM1/DFT electronic structure investigations and QSAR studies. Comput. Biology Chemistry 32 (2), 88–101. doi:10.1016/j.compbiolchem.2007.10.003
Waldhoer, M., Bartlett, S. E., and Whistler, J. L. (2004). Opioid receptors. Annu. Rev. Biochem. 73, 953–990. doi:10.1146/annurev.biochem.73.011303.073940
Wang, F. (1981). Alkaloids from roots of aconitum crassicaule.pdf. J. Med. Plant Res. 42, 375–379. doi:10.1055/s-2007-971658
Wang, J. (2004). Study on the structural modification of analgesics lappaconitine and bulleyaconitine and the oxidation of aliphatic cyclic ether to lactone. Chengdu, China: Sichuan University Press.
Wang, C. F., Gerner, P., Wang, S. Y., and Wang, G. K. (2007). Bulleyaconitine A isolated from aconitum plant displays long-acting local anesthetic properties in vitro and in vivo. Anesthesiology 107 (1), 82–90. doi:10.1097/01.anes.0000267502.18605.ad
Wang, C.-F., Gerner, P., Schmidt, B., Xu, Z. Z., Nau, C., Wang, S.-Y., et al. (2008). Use of bulleyaconitine A as an adjuvant for prolonged cutaneous analgesia in the rat. Anesth. & Analgesia 107 (4), 1397–1405. doi:10.1213/ane.0b013e318182401b
Wang, J.-L., Shen, X.-L., Chen, Q.-H., Qi, G., Wang, W., and Wang, F.-P. (2009). Structure–analgesic activity relationship studies on the C18-and C19-diterpenoid alkaloids. Chem. Pharm. Bull. 57 (8), 801–807. doi:10.1248/cpb.57.801
Wang, F.-P., Chen, Q.-H., and Liu, X.-Y. (2010). Diterpenoid alkaloids. Nat. Product. Rep. 27 (4), 529–570. doi:10.1039/b916679c
Wang, S., Li, K., Deng, Y., Gou, J., He, H., Yin, T., et al. (2024). Long-acting bulleyaconitine A microspheres via intra-articular delivery for multidimensional therapy of rheumatoid arthritis. Int. J. Pharm. 661, 124414. doi:10.1016/j.ijpharm.2024.124414
Wei, J., Wang, Y., and Kou, S. (2020). Mechanisms of bulleyaconitine A relieving pain in rats with neuropathic pain by regulating TRPV1 receptor function. HeBei Med. 26 (11), 1765–1770. doi:10.3969/j.issn.1006-6233.2020.11.02
Weng, W.-Y., Xu, H.-N., Huang, J.-M., Wang, G.-Q., Shen, T., and Zhang, J.-F. (2005). A pharmacokinetic study of intramuscular administration of bulleyaconitine A in healthy volunteers. Biol. Pharm. Bull. 28 (4), 747–749. doi:10.1248/bpb.28.747
Xiao, H., Ma, K., Huang, D., Liu, X. G., Liu, T. H., Liu, Q., et al. (2021). Expert consensus of the Chinese association for the study of pain on ion channel drugs for neuropathic pain. World J. Clin. Cases 9 (9), 2100–2109. doi:10.12998/wjcc.v9.i9.2100
Xiao, M., Huang, X.-h., and Ma, F.-l. (2025). Efficacy and safety of bulleyaconitine A in the treatment of osteoarthritis: a systematic review and meta-analysis. Medicine 104 (37), e44389. doi:10.1097/MD.0000000000044389
Xie, M.-X., Yang, J., Pang, R.-P., Zeng, W.-A., Ouyang, H.-D., Liu, Y.-Q., et al. (2018a). Bulleyaconitine A attenuates hyperexcitability of dorsal root ganglion neurons induced by spared nerve injury: the role of preferably blocking Nav1.7 and Nav1.3 channels. Mol. Pain 14, 1744806918778491. doi:10.1177/1744806918778491
Xie, M. X., Zhu, H. Q., Pang, R. P., Wen, B. T., and Liu, X. G. (2018b). Mechanisms for therapeutic effect of bulleyaconitine A on chronic pain. Mol. Pain 14, 1744806918797243. doi:10.1177/1744806918797243
Xiong, X., Zhai, S., and Yao, Z. (2009). Sensitive quantification of bulleyaconitine A in human serum by liquid chromatography-tandem mass spectrometry. Biosci. Biotechnol. Biochem. 73 (7), 1572–1577. doi:10.1271/bbb.90064
Xu, H., and Yao, J. (2023). Research progress on analgesic mechanism of bulleyaconitine A and its treatment of pain. Drugs & Clin. 38, 2639–2644. doi:10.7501/j.issn.1674-5515.2023.10.043
Yamada, H., Shimoyama, N., Sora, I., Uhl, G. R., Fukuda, Y., Moriya, H., et al. (2006). Morphine can produce analgesia via spinal kappa opioid receptors in the absence of mu opioid receptors. Brain Res. 1083 (1), 61–69. doi:10.1016/j.brainres.2006.01.095
Yang, X.-l., Yang, D.-n., Yang, Q.-r., Zhu, K., and Zhang, Y.-c. (2013). Research advances of bulleyaconitine A. World clinical drugs. 34 (2),
Yin, S.-L., Xu, F., Wu, H., Li, F., Jin, G., Wu, Z.-Q., et al. (2021). Safety assessment of aconitum-derived bulleyaconitine A: a 91-Day oral toxicity study and a tissue accumulation study in rats. World J. Traditional Chin. Med. 7 (2), 217–226. doi:10.4103/wjtcm.wjtcm_77_20
Zhan, X., Zhang, W., Sun, T., Feng, Y., Xi, Y., Jiang, Y., et al. (2019). Bulleyaconitine A effectively relieves allergic lung inflammation in a murine asthmatic model. Med. Sci. Monit. 25, 1656–1662. doi:10.12659/msm.915427
Zhang, R. X., Ahmed, T., Li, L. Y., Li, J., Abbasi, A. Z., and Wu, X. Y. (2017). Design of nanocarriers for nanoscale drug delivery to enhance cancer treatment using hybrid polymer and lipid building blocks. Nanoscale 9 (4), 1334–1355. doi:10.1039/c6nr08486a
Zhang, L., Feng, M., Li, Z., Zhu, M., Fan, Y., Chu, B., et al. (2018). Bulleyaconitine A prevents Ti particle-induced osteolysis via suppressing NF-κB signal pathway during osteoclastogenesis and osteoblastogenesis. J. Cell Physiol. 233 (9), 7067–7079. doi:10.1002/jcp.26508
Zhang, X., Shang, Y. S., Gao, F., Fang, D. M., Li, X. H., and Zhou, X. L. (2020). Synthesis and evaluation of a series of new bulleyaconitine A derivatives as analgesics. ACS Omega 5 (33), 21211–21218. doi:10.1021/acsomega.0c02944
Zhang, R., Wen, H., Lin, Z., Li, B., and Zhou, X. (2025). Artificial intelligence-driven drug toxicity prediction: advances, challenges, and future directions. Toxics 13 (7), 525. doi:10.3390/toxics13070525
Zhao, P., Tian, Y., Geng, Y., Zeng, C., Ma, X., Kang, J., et al. (2024). Aconitine and its derivatives: bioactivities, structure-activity relationships and preliminary molecular mechanisms. Front. Chem. 12, 1339364. doi:10.3389/fchem.2024.1339364
Keywords: analgesic mechanism, bulleyaconitine A, chronic pain, clinical application, novel drug delivery system, separation of toxicity and efficacy
Citation: Yin Z, Song X, Zhu C, Hou A and Chen R (2026) Analgesic effects of bulleyaconitine A: new advances in research from ion channel targets to clinical translation. Front. Pharmacol. 16:1733973. doi: 10.3389/fphar.2025.1733973
Received: 28 October 2025; Accepted: 26 December 2025;
Published: 15 January 2026.
Edited by:
David J. Adams, University of Wollongong, AustraliaReviewed by:
Sanjit Dey, University of Calcutta, IndiaMark T. Hamann, Medical University of South Carolina, United States
Copyright © 2026 Yin, Song, Zhu, Hou and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Rong Chen, MTg3MjUwOTIwMzRAMTYzLmNvbQ==
†These authors share first authorship