title: Peripheral analgesia and activation of the nitric oxide-cyclic GMP pathway.
abstract: We have previously described the analgesic effect of dibutyryl cyclic GMP or acetylcholine (ACh) injected into rat paws. Since ACh induces nitric oxide (NO) release from endothelial cells, we investigated the possible involvement of the NO-cyclic GMP pathway in ACh-induced analgesia, using a modification of the Randall-Selitto rat paw test. We found that sodium nitroprusside, which releases NO non-enzymatically, caused antinociception in the rat paw made hyperalgesic with prostaglandin E2. The analgesic effect of sodium nitroprusside and ACh was enhanced by intraplantar injection of an inhibitor of cyclic GMP phosphodiesterase (MY 5445) and was blocked by a guanylate cyclase inhibitor, methylene blue (MB). The analgesia induced by ACh, but not by sodium nitroprusside, was blocked by NG-monomethyl-L-arginine (L-NMMA), an inhibitor of the formation of NO from L-arginine. L-arginine itself had little or no effect upon prostaglandin-induced hyperalgesia but caused significant analgesia in paws inflamed with carrageenin. This analgesia was blocked by MB, as well as by L-NMMA, and was potentiated by MY 5445. These results suggest that ACh-induced analgesia was mediated via the release of NO. The results also indicate that the guanylate cyclase system is stimulated in the inflammatory reaction. The analgesia resulting from activation of this system is possibly overshadowed by substances that concomitantly stimulate nociceptor hyperalgesic mechanisms.
authors.affiliation: Department of Pharmacology, Faculdade de Medicina de Ribeiräo Preto, Sö Paulo, Brazil.
authors.forename: I D
authors.initials: ID
authors.lastname: Durate
authors.forename: B B
authors.initials: BB
authors.lastname: Lorenzetti
authors.forename: S H
authors.initials: SH
authors.lastname: Ferreira
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000109:Acetylcholine / Q000494:pharmacology / Q000502:physiology; D000698:Analgesia; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D009619:Nociceptors / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D019323:omega-N-Methylarginine
chemical_list: D000700:Analgesics; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D000109:Acetylcholine