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: J-S Lee, J Y Ro
• Journal: Neuroscience (Neuroscience) Vol. 146 Issue 1 Pg. 375-83 (Apr 25 2007) ISSN: 0306-4522 [Print] United States
• PMID: 17306466 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester
• Chromones
• Enzyme Inhibitors
• Excitatory Amino Acid Antagonists
• Pyridines
• Receptor, Metabotropic Glutamate 5
• Receptors, Metabotropic Glutamate
• Methoxyhydroxyphenylglycol
• 6-methyl-2-(phenylethynyl)pyridine
• Protein Kinase C
• 3,4-dihydroxyphenylglycol

Topics

• Analysis of Variance
• Animals
• Area Under Curve
• Behavior, Animal
• Chromones (pharmacology)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Excitatory Amino Acid Antagonists (pharmacology)
• Hyperalgesia (drug therapy, pathology)
• Male
• Masseter Muscle (drug effects, physiopathology)
• Methoxyhydroxyphenylglycol (analogs & derivatives, pharmacology)
• Pain Threshold (drug effects)
• Physical Stimulation (methods)
• Protein Kinase C (metabolism)
• Pyridines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptor, Metabotropic Glutamate 5
• Receptors, Metabotropic Glutamate (antagonists & inhibitors, physiology)