Recent Advances in the Modulation of Pain by the Metabotropic Glutamate Receptors

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2022 Aug 26

PMID 36010684

Authors

Mariacristina Mazzitelli

Peyton Presto

Nico Antenucci

Shakira Meltan

Volker Neugebauer

Affiliations

Soon will be listed here.

Abstract

Metabotropic glutamate receptors (mGluR or mGlu) are G-protein coupled receptors activated by the binding of glutamate, the main classical neurotransmitter of the nervous system. Eight different mGluR subtypes (mGluR1-8) have been cloned and are classified in three groups based on their molecular, pharmacological and signaling properties. mGluRs mediate several physiological functions such as neuronal excitability and synaptic plasticity, but they have also been implicated in numerous pathological conditions including pain. The availability of new and more selective allosteric modulators together with the canonical orthosteric ligands and transgenic technologies has led to significant advances in our knowledge about the role of the specific mGluR subtypes in the pathophysiological mechanisms of various diseases. Although development of successful compounds acting on mGluRs for clinical use has been scarce, the subtype-specific-pharmacological manipulation might be a compelling approach for the treatment of several disorders in humans, including pain; this review aims to summarize and update on preclinical evidence for the roles of different mGluRs in the pain system and discusses knowledge gaps regarding mGluR-related sex differences and neuroimmune signaling in pain.

Citing Articles

Anti-metabotropic glutamate receptor 5 coexistent anti-N-methyl-D-aspartate receptor encephalitis: a case report and literature review.

Gu Y, Xuan T, Li P, Zhou J, Wang Z Front Immunol. 2025; 16:1436246.

PMID: 40028323 PMC: 11867952. DOI: 10.3389/fimmu.2025.1436246.

NGF in Neuropathic Pain: Understanding Its Role and Therapeutic Opportunities.

Garcia-Dominguez M Curr Issues Mol Biol. 2025; 47(2).

PMID: 39996814 PMC: 11854882. DOI: 10.3390/cimb47020093.

Astragalin relieves inflammatory pain and negative mood in CFA mice by down-regulating mGluR5 signaling pathway.

Zhang R, Lin J, Wang S, Yang C, Zhou C, Yang Y Sci Rep. 2025; 15(1):5774.

PMID: 39962225 PMC: 11832914. DOI: 10.1038/s41598-025-90279-7.

Discovery of 4-(5-Membered)Heteroarylether-6-methylpicolinamide Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5.

Childress E, Capstick R, Crocker K, Ledyard M, Bender A, Maurer M ACS Med Chem Lett. 2024; 15(12):2210-2219.

PMID: 39691522 PMC: 11647725. DOI: 10.1021/acsmedchemlett.4c00481.

Microparticles Mediate Lipopolysaccharide-induced Inflammation and Chronic Pain in Mouse Model.

Singh A, Khushi , Tiwari V, Kumar A Neuromolecular Med. 2024; 26(1):48.

PMID: 39585502 DOI: 10.1007/s12017-024-08809-x.

References

Kiritoshi T, Neugebauer V . Group II mGluRs modulate baseline and arthritis pain-related synaptic transmission in the rat medial prefrontal cortex. Neuropharmacology. 2015; 95:388-94. PMC: 4466036. DOI: 10.1016/j.neuropharm.2015.04.003. View

Zuena A, Mairesse J, Casolini P, Cinque C, Alema G, Morley-Fletcher S . Prenatal restraint stress generates two distinct behavioral and neurochemical profiles in male and female rats. PLoS One. 2008; 3(5):e2170. PMC: 2366064. DOI: 10.1371/journal.pone.0002170. View

Palazzo E, Romano R, Luongo L, Boccella S, De Gregorio D, Giordano M . MMPIP, an mGluR7-selective negative allosteric modulator, alleviates pain and normalizes affective and cognitive behavior in neuropathic mice. Pain. 2015; 156(6):1060-1073. DOI: 10.1097/j.pain.0000000000000150. View

Vergne-Salle P, Bertin P . Chronic pain and neuroinflammation. Joint Bone Spine. 2021; 88(6):105222. DOI: 10.1016/j.jbspin.2021.105222. View

Ottani A, Leone S, Vergara F, Tacchi R, Loche A, Bertolini A . Preference for palatable food is reduced by the gamma-hydroxybutyrate analogue GET73, in rats. Pharmacol Res. 2007; 55(4):271-9. DOI: 10.1016/j.phrs.2006.12.002. View

Pamidimukkala J, Hoang C, Hay M . Expression of metabotropic glutamate receptor 8 in autonomic cell groups of the medulla oblongata of the rat. Brain Res. 2002; 957(1):162-73. DOI: 10.1016/s0006-8993(02)03619-3. View

Hosseini M, Parviz M, Shabanzadeh A, Zamani E, Mohseni-Moghaddam P, Gholami L . The inhibiting role of periaqueductal gray metabotropic glutamate receptor subtype 8 in a rat model of central neuropathic pain. Neurol Res. 2020; 42(6):515-521. DOI: 10.1080/01616412.2020.1747730. View

Soliman A, Yu J, Coderre T . mGlu and NMDA receptor contributions to capsaicin-induced thermal and mechanical hypersensitivity. Neuropharmacology. 2005; 48(3):325-32. DOI: 10.1016/j.neuropharm.2004.10.014. View

Notartomaso S, Scarselli P, Mascio G, Liberatore F, Mazzon E, Mammana S . N-Acetylcysteine causes analgesia in a mouse model of painful diabetic neuropathy. Mol Pain. 2020; 16:1744806920904292. PMC: 6997966. DOI: 10.1177/1744806920904292. View

10.

Marabese I, Rossi F, Palazzo E, de Novellis V, Starowicz K, Cristino L . Periaqueductal gray metabotropic glutamate receptor subtype 7 and 8 mediate opposite effects on amino acid release, rostral ventromedial medulla cell activities, and thermal nociception. J Neurophysiol. 2007; 98(1):43-53. DOI: 10.1152/jn.00356.2007. View

11.

Luongo L, de Novellis V, Gatta L, Palazzo E, Vita D, Guida F . Role of metabotropic glutamate receptor 1 in the basolateral amygdala-driven prefrontal cortical deactivation in inflammatory pain in the rat. Neuropharmacology. 2012; 66:317-29. DOI: 10.1016/j.neuropharm.2012.05.047. View

12.

Zammataro M, Chiechio S, Montana M, Traficante A, Copani A, Nicoletti F . mGlu2 metabotropic glutamate receptors restrain inflammatory pain and mediate the analgesic activity of dual mGlu2/mGlu3 receptor agonists. Mol Pain. 2011; 7:6. PMC: 3030510. DOI: 10.1186/1744-8069-7-6. View

13.

Boccella S, Marabese I, Iannotta M, Belardo C, Neugebauer V, Mazzitelli M . Metabotropic Glutamate Receptor 5 and 8 Modulate the Ameliorative Effect of Ultramicronized Palmitoylethanolamide on Cognitive Decline Associated with Neuropathic Pain. Int J Mol Sci. 2019; 20(7). PMC: 6480075. DOI: 10.3390/ijms20071757. View

14.

Vincent K, Wang S, Laferriere A, Kumar N, Coderre T . Spinal intracellular metabotropic glutamate receptor 5 (mGluR5) contributes to pain and c-fos expression in a rat model of inflammatory pain. Pain. 2016; 158(4):705-716. DOI: 10.1097/j.pain.0000000000000823. View

15.

Dolan S, Kelly J, Monteiro A, Nolan A . Up-regulation of metabotropic glutamate receptor subtypes 3 and 5 in spinal cord in a clinical model of persistent inflammation and hyperalgesia. Pain. 2003; 106(3):501-512. DOI: 10.1016/j.pain.2003.09.017. View

16.

Rovira X, Trapero A, Pittolo S, Zussy C, Faucherre A, Jopling C . OptoGluNAM4.1, a Photoswitchable Allosteric Antagonist for Real-Time Control of mGlu4 Receptor Activity. Cell Chem Biol. 2016; 23(8):929-34. DOI: 10.1016/j.chembiol.2016.06.013. View

17.

Liu N, Murugaiyan V, Storman E, Schnell S, Kumar A, Wessendorf M . Plasticity of Signaling by Spinal Estrogen Receptor α, κ-Opioid Receptor, and Metabotropic Glutamate Receptors over the Rat Reproductive Cycle Regulates Spinal Endomorphin 2 Antinociception: Relevance of Endogenous-Biased Agonism. J Neurosci. 2017; 37(46):11181-11191. PMC: 5688526. DOI: 10.1523/JNEUROSCI.1927-17.2017. View

18.

Gomez-Santacana X, Pittolo S, Rovira X, Lopez M, Zussy C, Dalton J . Illuminating Phenylazopyridines To Photoswitch Metabotropic Glutamate Receptors: From the Flask to the Animals. ACS Cent Sci. 2017; 3(1):81-91. PMC: 5269660. DOI: 10.1021/acscentsci.6b00353. View

19.

Zhang Y, Chen K, Sloan S, Bennett M, Scholze A, OKeeffe S . An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014; 34(36):11929-47. PMC: 4152602. DOI: 10.1523/JNEUROSCI.1860-14.2014. View

20.

Kung L, Gong K, Adedoyin M, Ng J, Bhargava A, Ohara P . Evidence for glutamate as a neuroglial transmitter within sensory ganglia. PLoS One. 2013; 8(7):e68312. PMC: 3699553. DOI: 10.1371/journal.pone.0068312. View