Therapeutic potential of group III metabotropic glutamate receptor ligands in pain
Introduction
Pain is one of the most common symptoms in clinical medicine and represents a permanent medical problem, being an essential component in the therapeutic management of many diseases. Pain can be classified as acute when it is short lasting or chronic when it persists for a long time after the original affection. Acute pain serves the important function of protecting the integrity of the body by detecting actual or potential tissue damage. Chronic pain is among the most debilitating and costly afflictions in North America and Europe, seriously affecting the quality of life of more than 19% of adult Europeans [1, 2, 3]. Unfortunately, while acute pain can be correctly managed, chronic pain is not efficiently alleviated by current treatments [4, 5, 6]. Therefore, a better understanding of cellular and molecular pathophysiological mechanisms is essential for identifying new pharmacological targets.
Glutamate is the main excitatory neurotransmitter of the mammalian central nervous system and is implicated in many physiological and pathological processes. Glutamate is notably the main neurotransmitter involved in pain transmission. At the synaptic level, glutamate activates two classes of receptors: ionotropic and metabotropic glutamate receptors (mGluRs). Central sensitization of the pain neuraxis is associated with hyperexcitability of the glutamatergic system and leads to the development of the evoked pain symptoms, allodynia (pain due to a stimulus that does not normally provoke pain) and hyperalgesia (increased pain from a stimulus that normally provokes pain) observed in patients with chronic pain [7]. Both iGluRs and mGluRs are involved in the induction and the maintenance of this sensitization. The blockade of increased glutamatergic activity may represent a pivotal mean to reduce chronic pain but awaits a clearer identification of adequate targets.
mGluRs are G-protein coupled receptors activated by glutamate, the major excitatory neurotransmitter of the central nervous system (CNS). They are involved in the modulation of synaptic activity. They are thus considered as potential therapeutic targets since less side effects are anticipated compared to essential actors of synaptic transmission.
The 8 members of this family are classified into 3 groups: Group I receptors (mGlu1 and 5) are post-synaptic and positively modulate glutamatergic transmission while group II (mGlu2 and 3) and group III receptors (mGlu4, 6, 7 and 8) are predominantly presynaptic and play an inhibitory role on neurotransmission (except for mGlu6, a post-synaptic receptor which is expressed solely in bipolar ON cells in the retina). Group III mGluRs can act either as autoreceptors on glutamatergic terminals or heteroreceptors on GABAergic terminals.mGluRs form constitutive dimers composed of two subunits cross-linked by a disulphide bridge. Dimer formation is mandatory for the function of these receptors [8]. It has long been believed that mGluRs strictly assemble into homodimers but a recent study has shown that certain mGluR subtypes can heterodimerize in vitro [9]. Heterodimerization could have consequences notably in terms of pharmacological profile, signaling response and protein partners. To date, there is no clear evidence of heterodimerization of mGluRs in vivo. However, recently, mGlu2/4 heterodimers have been suspected of existing at corticostriatal synapses, based on the detection of a unique pharmacological profile as compared to the mGlu2 or mGlu4 homodimers [10]. Since compatible mGluR subtypes coexist in several regions of the CNS, our comprehension of the regulation of CNS function by mGluRs, including pain, may evolve rapidly in the light of heterodimerization.
The different subtypes of mGluRs are expressed all along the pain neuraxis where they modulate the perception of pain (Figure 1). In general, blocking group-I mGluRs or activating group-II mGluRs alleviates pain (see [11, 12, 13] for recent reviews).
The present review will focus on group III mGluRs for which less information is available, mainly due to the lack of selective pharmacological tools. However, the recent progress in the development of subtype selective ligands is opening the way to a better understanding of their modulatory function and therapeutic potential in pain.
Section snippets
Group III mGluR pharmacology
As described in Figure 1, mGlu4, 7, 8 receptors of group III are localized all along the pain neuraxis. In order to investigate if these receptors may be novel therapeutic targets to reduce pain symptoms, various ligands were used (Figure 2, Table 1). However, interpretation of these experiments should take into consideration the limitations of these compounds. Most of the drugs that were evaluated are non-selective among the group III subtypes or display solubility issues or metabolic
Phenotypes of group III mGluRs knock-out mice
Mice lacking mGlu4 receptors display normal spontaneous motor activity but present an impaired ability to learn and memorize [62, 63]. The sensitivity to strong noxious mechanical compression is altered and the onset of the nociceptive behavior in the inflammatory phase of the formalin test is accelerated in mGlu4 KO mice as compared to their wild type littermates, whereas responses to punctate mechanical stimulation and nocifensive responses to thermal noxious stimuli are not modified [36••].
Localization and role of group III mGluRs in the pain neuraxis
The presence of group III mGluRs has been identified in different areas involved in pain processing (Figure 1), with the exception of mGlu6 which is exclusively expressed in the retina.
Conclusion
Taken together, these data suggest that group III mGluRs could be interesting therapeutic targets to alleviate chronic pain. Indeed, these receptors seem to be dedicated to the modulation of pain hypersensitivity and cognitive and emotional impairments observed in preclinical models of chronic pain. However, with the help of the novel selective pharmacological tools, further studies will be needed in order to clarify the precise roles of each subtype and their therapeutic potential.
Conflict of interest
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by grants from the Fondation pour la Recherche Médicale (FRM team DEQ20130326522), the Fundació La Marató de TV3 (Ref. 110232), Eranet Neuron and the Agence Nationale de la Recherche (ANR-12-NEUR-0003; ANR-13-BSV1-006). F.A. and C.G. were supported by the Centre National de la Recherche Scientifique (CNRS).
References (88)
- et al.
Prevalence of chronic pain with neuropathic characteristics in the general population
Pain
(2008) - et al.
Prevalence of chronic benign pain disorder among adults: a review of the literature
Pain
(1998) - et al.
Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment
Eur J Pain
(2006) - et al.
The evidence for pharmacological treatment of neuropathic pain
Pain
(2010) - et al.
Central sensitization: a generator of pain hypersensitivity by central neural plasticity
J Pain
(2009) - et al.
Dimers and beyond. The functional puzzles of class C GPCRs
Pharmacol Ther
(2011) - et al.
Metabotropic glutamate receptors and the control of chronic pain
Curr Opin Pharmacol
(2012) - et al.
The contribution of metabotropic glutamate receptors (mGluRs) to formalin-induced nociception
Pain
(1996) - et al.
Antinociceptive effects following intrathecal pretreatment with selective metabotropic glutamate receptor compounds in a rat model of neuropathic pain
Pharmacol Biochem Behav
(2002) - et al.
Low doses of cannabinoids enhance the antinociceptive effects of intracisternally administered mGluRs groups II and III agonists in formalin-induced TMJ nociception in rats
Pain
(2008)