Group III metabotropic glutamate receptors inhibit hyperalgesia in animal models of inflammation and neuropathic pain.
Glutamate plays a key role in modulation of nociceptive processing. This excitatory amino acid exerts its action through two distinct types of receptors, ionotropic and metabotropic glutamate receptors (mGluRs). Eight mGluRs have been identified and divided in three groups based on their sequence similarity, pharmacology and G-protein coupling. While the role of group I and II mGluRs is now well established, little is known about the part played by group III mGluRs in pain. In this work, we studied comparatively the involvement of spinal group III mGluR in modulation of acute, inflammatory and neuropathic pain. While intrathecal injection of ACPT-I, a selective group III mGluR agonist, failed to induce any change in vocalization thresholds of healthy animals submitted to mechanical or thermal stimuli, it dose-dependently inhibited the nociceptive behavior of rats submitted to the formalin test and the mechanical hyperalgesia associated with different animal models of inflammatory (carrageenan-treated and monoarthritic rats) or neuropathic pain (mononeuropathic and vincristine-treated rats). Similar effects were also observed following intrathecal injection of PHCCC, a positive allosteric modulator of mGlu4. Antihyperalgesia induced by ACPT-I was blocked either by LY341495, a nonselective antagonist of mGluR, by MAP4, a selective group III antagonist. This study provide new evidences supporting the role of spinal group III mGluRs in the modulation of pain perception in different pathological pain states of various etiologies but not in normal conditions. It more particularly highlights the specific involvement of mGlu4 in this process and may be a useful therapeutic approach to chronic pain treatment.
Goudet
Cyril
C
Univ Montpellier I& II, CNRS UMR5203, Institut de Génomique Fonctionnelle, 141 Rue de la Cardonille, F-34094 Montpellier Cedex 5, France INSERM, U661, Montpellier, F-34094, France INSERM, UMR766, Pharmacologie Fondamentale et Clinique de la Douleur, Clermont-Ferrand, F-63001, France Univ Clermont 1, Faculté de Médecine, Laboratoire de Pharmacologie Médicale, Clermont-Ferrand, F-63001, France CHU Clermont-Ferrand, Service de Pharmacologie, Clermont-Ferrand, F-63003, France UMR8601-CNRS, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris V, 45 rue des Saints-Pères, 75270 Paris 06, France.
Chapuy
Eric
E
Alloui
Abdelkrim
A
Acher
Francine
F
Pin
Jean-Philippe
JP
Eschalier
Alain
A
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006930:Hyperalgesia / Q000503:physiopathology / Q000517:prevention & control*; D007249:Inflammation / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D009437:Neuralgia / Q000503:physiopathology / Q000517:prevention & control*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000502:physiology*
D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; C102718:metabotropic glutamate receptor 3