title: Peripheral metabotropic glutamate receptor 5 mediates mechanical hypersensitivity in craniofacial muscle via protein kinase C dependent mechanisms.
abstract: We previously demonstrated that peripherally located N-methyl-D-aspartic acid (NMDA) receptors contribute to acute muscle nociception and the development of chronic muscular hyperalgesia. In the present study, we investigated the potential role of peripheral group I metabotropic glutamate receptors (mGluRs 1/5) in the development of muscular hypersensitivity to mechanical stimulation, and attempted to elucidate intracellular signaling mechanisms associated with the mGluR activation in male Sprague-Dawley rats. First, our Western blot analyses revealed that mGluR 5 protein, but not mGluR 1 protein, is reliably detected in trigeminal ganglia and the masseter nerve. Subsequent behavioral studies demonstrated that the group I mGluR agonist, R,S-3,5-dihydroxyphenylglycol (DHPG), significantly decreased the mechanical threshold to noxious stimulation of the masseter, and that the DHPG-induced mechanical hypersensitivity can be effectively prevented by pretreatment of the masseter with 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), a selective mGluR 5 antagonist, but not by 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt), a selective mGluR 1 antagonist. Moreover, the DHPG-induced mechanical hypersensitivity was significantly blocked by inhibiting either the alpha or epsilon isoform of protein kinase C (PKC). Collectively, these data provide evidence that peripherally located mGluR 5 may play an important role in the development of masseter hypersensitivity, and that PKC activation is required for the modulatory effect of peripheral mGluR 5 in the craniofacial muscle tissue. Thus, selective targeting of peripheral mGluR 5 and PKCalpha, as well as PKCepsilon, might serve as an effective therapeutic strategy in the management of chronic muscle pain conditions, such as temporomandibular disorders.
authors.affiliation: Department of Biomedical Sciences, Program in Neuroscience, University of Maryland Baltimore School of Dentistry, 650 West Baltimore Street, Baltimore, MD 21201, USA.
authors.forename: J-S
authors.initials: JS
authors.lastname: Lee
authors.forename: J Y
authors.initials: JY
authors.lastname: Ro
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D001522:Behavior, Animal; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006930:Hyperalgesia / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D008406:Masseter Muscle / Q000187:drug effects / Q000503:physiopathology*; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D017288:Pain Threshold / Q000187:drug effects; D010812:Physical Stimulation / Q000379:methods; D011493:Protein Kinase C / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: C117789:7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester; D002867:Chromones; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D008734:Methoxyhydroxyphenylglycol; C121465:6-methyl-2-(phenylethynyl)pyridine; D011493:Protein Kinase C; C010117:3,4-dihydroxyphenylglycol