title: Peripheral group I metabotropic glutamate receptor activation leads to muscle mechanical hyperalgesia through TRPV1 phosphorylation in the rat.
abstract: Elevated glutamate levels within injured muscle play important roles in muscle pain and hyperalgesia. In this study, we hypothesized that protein kinase C (PKC)-dependent TRPV1 phosphorylation contributes to the muscle mechanical hyperalgesia following activation of Group I metabotropic glutamate receptors (mGlu1/5). Mechanical hyperalgesia induced by (R,S)-3,5-dihydroxyphenylglycine (DHPG), an mGlu1/5 agonist, in the masseter muscle was attenuated by AMG9810, a specific TRPV1 antagonist. AMG9810 also suppressed mechanical hyperalgesia evoked by pharmacologic activation of PKC. DHPG-induced mechanical hyperalgesia was suppressed by pretreatment with a decoy peptide that disrupted interactions between TRPV1 and A-kinase-anchoring protein (AKAP), which facilitates phosphorylation of TRPV1. In dissociated trigeminal ganglia, DHPG upregulated serine phosphorylation of TRPV1 (S800), during which DHPG-induced mechanical hyperalgesia was prominent. The TRPV1 phosphorylation at S800 was suppressed by a PKC inhibitor. Electrophysiologic measurements in trigeminal ganglion neurons demonstrated that TRPV1 sensitivity was enhanced by pretreatment with DHPG, and this was prevented by a PKC inhibitor, but not by a protein kinase A inhibitor. These results suggest that mGlu1/5 activation in masseter afferents invokes phosphorylation of TRPV1 serine residues including S800, and that phosphorylation-induced sensitization of TRPV1 is involved in masseter mechanical hyperalgesia. These data support a role of TRPV1 as an integrator of glutamate receptor signaling in muscle nociceptors.
  
  
  CONCLUSIONS
  This article demonstrates that activation of mGlu1/5 leads to phosphorylation of a specific TRPV1 residue via PKC and AKAP150 in trigeminal sensory neurons and that functional interactions between glutamate receptors and TRPV1 mediate mechanical hyperalgesia in the muscle tissue.
authors.affiliation: Department of Neural and Pain Sciences, Program in Neuroscience, University of Maryland School of Dentistry, Baltimore, Maryland.
authors.forename: Man-Kyo
authors.initials: MK
authors.lastname: Chung
authors.affiliation: Department of Neural and Pain Sciences, Program in Neuroscience, University of Maryland School of Dentistry, Baltimore, Maryland.
authors.forename: Jongseok
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Neural and Pain Sciences, Program in Neuroscience, University of Maryland School of Dentistry, Baltimore, Maryland.
authors.forename: John
authors.initials: J
authors.lastname: Joseph
authors.affiliation: Department of Neural and Pain Sciences, Program in Neuroscience, University of Maryland School of Dentistry, Baltimore, Maryland.
authors.forename: Jami
authors.initials: J
authors.lastname: Saloman
authors.affiliation: Department of Neural and Pain Sciences, Program in Neuroscience, University of Maryland School of Dentistry, Baltimore, Maryland. Electronic address: jro@umaryland.edu.
authors.forename: Jin Y
authors.initials: JY
authors.lastname: Ro
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D005998:Glycine / Q000031:analogs & derivatives; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D008406:Masseter Muscle / Q000503:physiopathology; D063806:Myalgia / Q000188:drug therapy / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D012118:Resorcinols; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014110:Touch; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000503:physiopathology
chemical_list: D054758:A Kinase Anchor Proteins; C415703:Akap5 protein, rat; C578937:Grm5 protein, rat; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C104077:metabotropic glutamate receptor type 1; C079215:3,5-dihydroxyphenylglycine; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D005998:Glycine
keywords: Peripheral; muscle pain; sensory neurons; trigeminal