title: Alleviating pain hypersensitivity through activation of type 4 metabotropic glutamate receptor.
abstract: Hyperactivity of the glutamatergic system is involved in the development of central sensitization in the pain neuraxis, associated with allodynia and hyperalgesia observed in patients with chronic pain. Herein we study the ability of type 4 metabotropic glutamate receptors (mGlu4) to regulate spinal glutamate signaling and alleviate chronic pain. We show that mGlu4 are located both on unmyelinated C-fibers and spinal neurons terminals in the inner lamina II of the spinal cord where they inhibit glutamatergic transmission through coupling to Cav2.2 channels. Genetic deletion of mGlu4 in mice alters sensitivity to strong noxious mechanical compression and accelerates the onset of the nociceptive behavior in the inflammatory phase of the formalin test. However, responses to punctate mechanical stimulation and nocifensive responses to thermal noxious stimuli are not modified. Accordingly, pharmacological activation of mGlu4 inhibits mechanical hypersensitivity in animal models of inflammatory or neuropathic pain while leaving acute mechanical perception unchanged in naive animals. Together, these results reveal that mGlu4 is a promising new target for the treatment of chronic pain.
authors.affiliation: Institut de Génomique Fonctionnelle, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203, Université de Montpellier, F-34094 Montpellier, France, Institut National de la Santé et de la Recherche Médicale, U661, F-34094 Montpellier, France, Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, F-63000 Clermont-Ferrand, France, Inserm, U 1107, Neuro-Dol, F-63001 Clermont-Ferrand, France, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8601, Université Paris Descartes, Sorbonne Paris Cité, F-75270 Paris, France, and CHU Clermont-Ferrand, Service de pharmacologie, F-63003 Clermont-Ferrand, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vilar
authors.forename: Jérôme
authors.initials: J
authors.lastname: Busserolles
authors.forename: Bing
authors.initials: B
authors.lastname: Ling
authors.forename: Sophie
authors.initials: S
authors.lastname: Laffray
authors.forename: Lauriane
authors.initials: L
authors.lastname: Ulmann
authors.forename: Fanny
authors.initials: F
authors.lastname: Malhaire
authors.forename: Eric
authors.initials: E
authors.lastname: Chapuy
authors.forename: Youssef
authors.initials: Y
authors.lastname: Aissouni
authors.forename: Monique
authors.initials: M
authors.lastname: Etienne
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bourinet
authors.forename: Francine
authors.initials: F
authors.lastname: Acher
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Pin
authors.forename: Alain
authors.initials: A
authors.lastname: Eschalier
authors.forename: Cyril
authors.initials: C
authors.lastname: Goudet
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002351:Carrageenan; D002908:Chronic Disease; D003251:Constriction, Pathologic / Q000473:pathology; D055724:Electrophysiological Phenomena / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000627:therapeutic use*; D005455:Fluorescent Antibody Technique; D006930:Hyperalgesia / Q000188:drug therapy*; D007101:Immersion / Q000503:physiopathology; D007395:Interneurons / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000502:physiology; D010147:Pain Measurement / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010721:Phosphinic Acids / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics; D019051:Rhizotomy; D011984:Sensory Receptor Cells / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D018690:Excitatory Amino Acid Agonists; C572429:LSP4-2022; D010721:Phosphinic Acids; D018094:Receptors, Metabotropic Glutamate; D002351:Carrageenan; C108823:metabotropic glutamate receptor 4
keywords: GPCR; allodynia; analgesia; hyperalgesia; mGlu; pain