Systemic administration of mGlu1 receptor antagonists are inefficient at altering normal pain threshold in naive animals (Maione et al., 1998; Sevostianova and Danysz, 2006). However, mGlu1 receptor inhibition relieves both mechanical and thermal hypersensitivity in various models of both inflammatory and neuropathic pain (Table 1) (Varty et al., 2005; El-Kouhen et al., 2006; Sevostianova and Danysz, 2006; Satow et al., 2008; Zhu et al., 2008). Similarly, systemic administration of mGlu5 receptor antagonists fails to modify basal thermal threshold (Sevostianova and Danysz, 2006), whereas it prevents mechanical and thermal hyperalgesia in a broad range of pain conditions from sub-chronic inflammatory pain to long lasting neuropathic pain (Table 1) (Walker et al., 2001a,b; Hudson et al., 2002; Zhu et al., 2004; Varty et al., 2005; Sevostianova and Danysz, 2006; Satow et al., 2008; Jacob et al., 2009; Montana et al., 2009; Zammataro et al., 2011). Of note, mGlu1 receptor inhibition induces motor and cognitive side effects at analgesic doses that could limit its use in clinical trials (El-Kouhen et al., 2006; Zhu et al., 2008). Consequently, mGlu5 receptor seems to be a better target to develop analgesic drugs. Although mGlu5 antagonists have been reported to induce tolerance and some locomotor deficits (Varty et al., 2005; Sevostianova and Danysz, 2006), it is interesting to point out that mGlu5 receptor antagonists reduce anxiety in naïve animals, a comorbidity often associated with chronic pain states (Varty et al., 2005).

Systematically administrated group II selective agonists have proven anti-hyperalgesic effects in both inflammatory and neuropathic pain without altering basal pain thresholds in healthy animals (Table 2) (Sharpe et al., 2002; Simmons et al., 2002; Satow et al., 2008; Johnson et al., 2017). Interestingly, selective group II mGluRs agonists have entered into clinical trials for the treatment of schizophrenia suggesting a safe profile of the drug in humans (Li et al., 2015; Muguruza et al., 2016).

Only a few studies have investigated the effect of systemic administration of group III selective compounds in pain perception (Table 3). Systemic delivery of mGlu4 receptor agonist alleviates mechanical hypersensitivity provoked by carrageenan-induced inflammation (Vilar et al., 2013). AMN082, an mGlu7 receptor PAM prevents hyperalgesia in inflammatory models (Dolan et al., 2009). The same compound injected systematically reduces mechanical allodynia and thermal hyperalgesia induced by chronic constriction injury to the sciatic nerve and potentiates the effect of morphine (Osikowicz et al., 2008). This drug also exhibits antidepressant-like and anxiolytic-like effects (Bradley et al., 2012). In addition to the mGlu7 receptor, other mechanisms can contribute to these effects since the AMN082 compound is rapidly metabolized in vivo into a monoamine transporter inhibitor (Sukoff Rizzo et al., 2011). Surprisingly, systemically administrated mGlu7 receptor negative allosteric modulators (NAMs) also have anti-hyperalgesic effects in neuropathic pain models (Palazzo et al., 2015). As detailed further in this review, pharmacological activation of mGlu7 receptors can lead to opposite effects depending on the administration site. Neuropathic pain induces variation in mGlu7 receptor expression that could imbalance the pronociceptive and antinociceptive role of mGlu7 receptor (Osikowicz et al., 2009; Palazzo et al., 2013, 2015).

Systemic delivery of a mGlu8 receptor agonist also decreases nociceptive responses in inflammatory and neuropathic models, which is inhibited by blocking group III mGluRs in the PAG (Marabese et al., 2007).

Group I mGlu1 and mGlu5 receptors are expressed in nociceptive afferents (Bhave et al., 2001; Walker et al., 2001a,b). Together with iGluR, group I mGluRs are involved in capsaicin induced glutamate release, a process that could contribute to nociceptive responses evoked by the TRPV1 agonist (Jin et al., 2009). Intraplantar injection of group I agonists in rodents enhances thermal sensitivity and reciprocally, peripherally applied group I antagonist reduced hyperalgesia in animal models of inflammatory or neuropathic pain (Table 4) (Dogrul et al., 2000; Bhave et al., 2001; Walker et al., 2001a,b). Application of mGlu5 receptor antagonist at peripheral afferent endings also reduces visceral nociception (Table 5) (Lindström et al., 2008). More recently, the analgesic potential of peripheral mGlu5 receptor blockade has been highlighted using an mGlu5 selective photoactivable NAM. Photoactivable ligands, also called caged-ligands, are constituted of a ligand linked to a photo-labile protecting group that will be removed following illumination, enabling the precise control of the onset of drug activity at a specific location (Goudet et al., 2018). Following systemic injection of the inactive caged-mGlu5 NAM, analgesia in both phases of the formalin test can be induced by local illumination in the paw (Table 5) (Font et al., 2017).

Primary sensory neurons express mGlu2 and mGlu3 receptors in both peripheral terminals and dorsal horn projection (Carlton et al., 2001; Carlton and Hargett, 2007). In DRG, mGlu2/3 receptors are largely co-localized with TRPV1 channel (Carlton et al., 2009). Consistent with this co-expression, group II mGluR antagonists increase hyperalgesia evoked by capsaicin, a TRPV1 agonist, and this effect is blocked by group II mGluR agonists (Table 6) (Carlton et al., 2011). However, a recent report has demonstrated that mGlu2/3 receptors activation abolishes TRPV1 sensitization in mouse sensory neurons, but not in humans (Sheahan et al., 2018).

In cultured DRG neurons, group II mGluRs also negatively regulate TTX resistant sodium channels (Yang and Gereau, 2004). Local administration of group II agonist in the knee joint both prevents and reduces carrageenan-induced arthritis (Lee et al., 2013). Due to the lack of selective compounds that can discriminate between mGlu2 and mGlu3 receptors, the individual contribution of those two receptors to pain modulation has remained unclear for a long time. However, the generation of mGlu2 and mGlu3 receptor knockout mice allowed the precise investigation of the role of each subtype in nociception and revealed a predominant role of the mGlu2 over mGlu3 receptor (Zammataro et al., 2011).

In line with the pharmacological evidence, mGlu2 receptor overexpression in DRG induces analgesia in models of inflammatory and neuropathic pain (Chiechio et al., 2002, 2009). L-acetylcarnitine, a drug known to enhance mGlu2 receptor expression in DRG through epigenetic mechanisms induces a long-lasting analgesia in both inflammatory and neuropathic pain models (Notartomaso et al., 2017). Strikingly, N-acetyl-cysteine, a drug enhancing mGlu2 receptor expression in rodents, reduces nociceptive transmission in humans (Truini et al., 2015). Moreover, in a recent report using cultured DRG neurons from both mice and humans, PGE2 evoked neuron hyperexcitability was blocked by group II mGluR activation (Davidson et al., 2016). This data suggests that activation of group II mGluRs leads to an analgesic effect in rodents and humans, making group II mGluRs an interesting target for development of peripherally active drugs for the treatment of chronic pain.

Most group III mGluRs are expressed in the pain pathway, except the mGlu6 receptor which is expressed mainly in the retina (Vardi et al., 2000). The presence of mGlu4, mGlu7, and mGlu8 receptors have been detected in DRG and trigeminal ganglia (Li et al., 1996; Azkue et al., 2001; Carlton and Hargett, 2007). The mGlu8 receptor is expressed in DRG and peripheral terminals where it is widely co-expressed with TRPV1. Intraplantar injection of group III agonists significantly reduced capsaicin evoked pain behavior (Table 7; Govea et al., 2012). Similar to group II agonists, local administration in the knee joint of group III mGluRs agonist provokes analgesia in carrageenan-induced arthritic pain model (Lee et al., 2013). Specific contribution of each subtype to the antinociceptive effect of broad range group III mGluRs need to be further investigated.

Immunoreactive cell bodies for group I mGluRs are widely spread throughout the superficial laminae of DH (Jia et al., 1999; Tang and Sim, 1999; Hudson et al., 2002). Intrathecal administration of group I mGluR agonists provokes hyperalgesia whereas group I mGluR antagonists induces analgesia in inflammatory and neuropathic pain models (Table 4) (Fisher and Coderre, 1996, 1998; Young et al., 1997; Fisher et al., 1998). Intrathecal injection of mGlu5 antagonist also reverses paclitaxel-induced neuropathic pain (Table 5; Xie et al., 2017). DH neuron excitability is increased after activation of spinal group I mGluRs in part due to due to inhibition of a voltage gated potassium channel (Hu et al., 2007). In line with this pharmacological evidence, knockdown or antibody approaches targeting mGlu1 receptor have demonstrated an antinociceptive effect in various pain models (Fundytus et al., 1998, 2001; Noda et al., 2003). Interestingly, recent studies have reported enhanced mGlu5 expression at the nuclear membrane in DH neurons after nerve injury. Using permeable mGlu5 antagonists reaching the cytoplasm, the authors have demonstrated that blocking intracellular mGlu5 had a greater antinociceptive effect than by blocking cell membrane expressed mGlu5 (Vincent et al., 2016). Pre-treatment with an excitatory amino acid transporter (EAAT) inhibitor, which is meant to decrease intracellular glutamate levels, decreases pain-related behavior in an inflammatory pain model (Vincent et al., 2017).

Among group II mGluRs, mGlu3 receptor is the most expressed in the DH, and its transcript is restricted to laminae II (Valerio et al., 1997; Berthele et al., 1999; Jia et al., 1999). However, only mGlu2 receptor expression appears to be enhanced in the SC (and DRG neurons) after administration of L-acetylcarnitine and histone deacetylase inhibitors, two compounds with antinociceptive properties, suggesting a greater role of spinal mGlu2 receptors in pain modulation (Chiechio et al., 2002, 2009). This discrepancy could be explained by expression pattern differences. Indeed, mGlu2 receptor is mostly pre-synaptic, while mGlu3 receptor is both pre- and post-synaptic (Nicoletti et al., 2011). Moreover, mGlu2 is expressed in microglia while mGlu3 is expressed in both microglia and astrocytes (Spampinato et al., 2018).

Transcripts of two group III members, mGlu4 and mGlu7 receptors, are detected in the spinal cord (Valerio et al., 1997). The expression of mGlu4 receptor is restricted to inner laminae II of the DH receiving nociceptive Aδ- and C-fibers inputs whereas mGlu7 receptor is expressed in both laminae I and II (Valerio et al., 1997; Vilar et al., 2013). In addition, the mGlu4 receptor may be expressed in spinal neurons, since its expression can still be observed after rhizotomy of the afferent fibers (Vilar et al., 2013). Activation of spinal group III mGluRs depletes glutamate release from primary afferents in nerve-injured rats (Table 7; Zhang et al., 2009). Furthermore, intrathecal administration of the group III broad-spectrum agonist L-AP4 reduces capsaicin-induced hypersensitivity and neuropathic pain symptoms (Fisher et al., 2002; Chen and Pan, 2005; Soliman et al., 2005). Intrathecal administration of the mGlu4 receptor PAM or agonist inhibits both inflammatory and neuropathic pain without altering acute pain thresholds in naive animals (Table 8; Goudet et al., 2008; Wang et al., 2011; Vilar et al., 2013). Conversely, the antiallodynic action of an mGlu4 agonist in inflammatory pain can be blocked by a photoswitchable mGlu4 NAM (Rovira et al., 2016). Positive allosteric modulation of spinal mGlu7 alleviates mechanical allodynia and thermal hyperalgesia induced by either carrageenan or skin incisions (Dolan et al., 2009). However, intrathecally administrated mGlu7 PAM has failed to relieve neuropathic pain (Wang et al., 2011). Both studies used the mGlu7 PAM named AMN082 (Mitsukawa et al., 2005). As mentioned earlier in the text, in vivo, AMN082 is rapidly metabolized and one of its metabolite inhibits several monoamine transporters (Sukoff Rizzo et al., 2011). Therefore, in vivo actions of AMN082 should be interpreted with caution since it may have multiple mode of action.

Although it is clearly established that activation of group I mGluRs at both the periphery and the spinal cord promotes pain, group I activation at the supraspinal level can elicit both antinociceptive and pronociceptive effects depending on the region investigated (Tables 4, 5). For instance, when applied in the amygdala, group I agonist promotes nociception (Li and Neugebauer, 2004; Kolber et al., 2010; Ren and Neugebauer, 2010; Tappe-Theodor et al., 2011). Reciprocally, stereotaxic injection of mGlu1 and mGlu5 receptor antagonists in the amygdala inhibits pain-related responses in a model of arthritic pain (Han and Neugebauer, 2005). Similarly, intra basolateral amygdala administration of group I mGluRs agonist alleviates inflammatory pain, an effect at least in part due to inhibition of prefrontal cortex neurons activity (Luongo et al., 2013). When applied to the thalamus, mGlu1 PAM potentiated nociceptive responses of thalamic neurons (Salt et al., 2014). Conversely, when administrated in the PAG, a region involved in modulation of the descending pain pathway, activation of group I mGluRs decreases the nociceptive response, likely through the inhibition of the GABAergic transmission (Maione et al., 2000; Drew and Vaughan, 2004). Moreover, PAG expressed mGlu5 contribute to the antinociceptive effect provoked by RVM cannabinoid receptor activation (de Novellis et al., 2005).

In an outstanding paper, authors used a selective photoactivable mGlu5 NAM enabling the precise spatiotemporal modulation of mGlu5 receptors to probe the involvement of thalamic mGlu5 receptors in pain processing. As expected, when injected systematically, the inactive caged compound has no effect on pain behavior of neuropathic animals. However, release of the active mGlu5 NAM by delivering light through implanted optical fibers in the ventrobasal thalamus, reduces neuropathic pain (Font et al., 2017).

An alternative photopharmacological strategy consists in using photoswitchable ligands that can be reversibly activated and inactivated by light (Goudet et al., 2018). This approach has been used to validate the role of amygdala-expressed mGlu5 in pain. A photoswitchable mGlu5 NAM has been injected locally in amygdala where it light-dependently reduced mechanical allodynia in a mice model of inflammatory pain (Gómez-Santacana et al., 2017), confirming previous preclinical studies (Han and Neugebauer, 2005).

Interestingly, global genetic disruption of mGlu5 in mice leads to increased basal mechanical withdrawal responses whereas conditional KO in the amygdala did not affect acute pain. However, both global and conditional KO prevent the establishment of mechanical hypersensitivity 180 min after formalin injection in the ipsi and contralateral paw (Kolber et al., 2010).

Accumulating evidence demonstrates that stimulation of group II mGluRs in supraspinal areas mediates analgesia (Table 6). Administration into the amygdala by microdialysis of group II agonist diminishes the response to noxious stimulation in an arthritis model of chronic pain (Li and Neugebauer, 2006). In the PAG, group II mGluR activation reinforces antinociceptive descending pathway (Maione et al., 2000). Local inhibition in the PAG or the RVM of the degradation of an endogenous peptide acting as an mGlu3 receptor agonist relieves pain in rat models of inflammatory and neuropathic pain (Yamada et al., 2012). However, studies have also reported a pronociceptive effect of CNS expressed group II mGluRs. For instance, blockage in the thalamus elicits antinociceptive effects, possibly via an inhibition of GABAergic inhibitory neurones (Neto and Castro-Lopes, 2000). Furthermore, microinjection of a group II agonist in the PAG induces pronociceptive effects by inhibiting descending pathway (Maione et al., 1998).

Broad range group III mGluR agonists were first used to elucidate the contribution of these receptors in pain processing in the CNS (Table 7). Early studies demonstrated that in the PAG a group III mGluR agonist facilitates pain related behavior (Maione et al., 1998, 2000), whereas in the amygdala group III agonist microinjection produces antinociceptive effects in an arthritis model (Li and Neugebauer, 2006). Development of more selective compounds for individual group III subtypes has allowed the more precise dissection of each members' contribution to nocifensive and affective pain responses within the CNS (Table 8). Of note, mGlu7 and mGlu8 have opposite effects in the PAG. Indeed, mGlu7 activation in PAG and amygdala is pronociceptive whereas mGlu8 activation is antinociceptive (Marabese et al., 2007; Palazzo et al., 2008). Similarly, in the nucleus tractus solitarius, mGlu7 activation has an antinociceptive effect on the cardiac-somatic reflex induced by pericardial capsaicin, while activation of mGlu8 receptors enhance cardiac nociception (Liu et al., 2012). Activation of mGlu7 in the nucleus accumbens by AMN082 has an antinociceptive effect and modulates relief learning (Kahl and Fendt, 2016). Blockade of mGlu7 in the PAG reduces the pain related behaviors in formalin and neuropathic pain models and differentially modulates RVM ON and OFF cell activity (Palazzo et al., 2013). Whereby, ON cells are neurons activated by noxious stimuli and inhibited by analgesics, and OFF cells are activated by analgesics and inhibited by painful stimuli (Palazzo et al., 2013).

Recently, dorsal striatum (DS) expressed mGlu7 receptors and their role in pain have been investigated. The DS is connected to the descending pain modulatory systems, including to the RVM. When locally administrated in the DS of sham animals, an mGlu7 PAM enhanced pain and simultaneously stimulates ON cells and inhibits OFF cells in the RVM. Whereas, in nerve-injured animals, the mGlu7 PAM has an anti-hyperalgesic effect in addition to increasing RVM OFF cell firing. This opposite effect of an mGluR7 PAM in acute or chronic pain conditions is assumed to be due to the recruitment of different pain pathways (Marabese et al., 2018). Interestingly, systemic administration of an mGluR7 PAM prevents the development of morphine tolerance (Gawel et al., 2018). A role of centrally expressed mGlu7 in epilepsy has also been reported (Sansig et al., 2001; Bertaso et al., 2008).

The first strong evidence of supraspinal mGlu4 involvement in pain processing is thanks to the recent development of an mGlu4 photoswitchable PAM allowing the time resolved control of endogenous receptors in freely behaving animals. Strikingly, dynamic modulation of mGlu4 receptor activation in the amygdala by the photoswitchable PAM reverses, in a light dependent manner, both inflammatory pain-related sensory and affective symptoms (Zussy et al., 2018). As compared to conventional compounds, this ligand enables precise temporal control of the mGlu4 receptor and, in contrast to optogenetics, allows endogenous receptor modulation, without the need of trangenesis. We expect that future development of photoswitchable ligands for other mGluRs will greatly improve our understanding of mGluRs in the pain neuraxis and co-morbidities associated with chronic pain conditions.

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.