Peripheral group II metabotropic glutamate receptors (mGluR2/3) regulate prostaglandin E2-mediated sensitization of capsaicin responses and thermal nociception.
Previous studies have shown that group II metabotropic glutamate receptors (mGluRs) are present on the peripheral terminals of primary sensory neurons, suggesting that they might be involved in nociception. In this study, we investigated the modulation of nociception by peripheral group II mGluRs and the molecular basis of this modulation. Subcutaneous injection of a group II mGluR agonist, 2R,4R 4-aminopyrrolidine-2,4-dicarboxylate (APDC), did not alter thermal sensitivity but blocked prostaglandin E2 (PGE2)-induced thermal hyperalgesia. This effect was blocked by (2s)-2-amino-2-[(1s,2s)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid, a selective group II mGluR antagonist. In cultured primary sensory neurons, APDC blocked PGE2-induced potentiation of capsaicin responses, which was abolished when neurons were pretreated with pertussis toxin. Similar potentiating effects induced by forskolin but not 8-bromo-cAMP were also blocked by the activation of group II mGluRs. These results indicate that peripheral group II mGluRs act via inhibition of adenylyl cyclase to reverse the sensitization of capsaicin receptors and the thermal hyperalgesia induced by PGE2, and suggest that peripheral group II mGluRs might be targeted for therapeutic intervention in inflammatory pain states.
Yang
Dongni
D
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
Gereau
Robert W
RW
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism* / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009475:Neurons, Afferent / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D037342:Pertussis Toxin; D010766:Phosphorylation / Q000187:drug effects; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D011955:Receptors, Drug / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
C097299:4-aminopyrrolidine-2,4-dicarboxylic acid; D037361:Adenylate Cyclase Toxin; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D011955:Receptors, Drug; D018094:Receptors, Metabotropic Glutamate; D010566:Virulence Factors, Bordetella; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D011392:Proline; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000262:Adenylyl Cyclases; D015232:Dinoprostone; D002211:Capsaicin