Molecular base of acetylcholine and morphine analgesia.
We have previously described the peripheral analgesic effect of dibutyryl cyclic GMP, acetylcholine (ACh) and morphine (Mph) injected into the rat paws. Since ACh induces nitric oxide (NO) release from endothelial cells which is though to stimulate guanylate cyclase (GC) we investigated if NO-cyclic GMP pathway was involved in the analgesia by those agents. Using a modification of the Randall-Selitto rat paw test, it was found that sodium nitroprusside, which releases NO non-enzymatically, blocked rat paw PGE2 induced hyperalgesia. The peripheral analgesic effect of sodium nitroprusside, ACh and morphine was enhanced by intraplantar injection of an inhibitor of cyclic GMP phosphodiesterase (MY5445) and blocked by a GC inhibitor, methylene blue (MB). Peripheral analgesia induced by ACh and morphine, but not by sodium nitroprusside, was blocked by NG-monomethyl-L-arginine (L-NMMA) an inhibitor of the formation of NO from L-arginine. Central effect of morphine as tested by the rat paw and by the tail flick tests was inhibited by intraventricular injection of methylene blue. In addition, the central morphine analgesia was potentiated by My5445. In contrast, with the periphery, the central effect of morphine was not blocked by L-NMMA. Our results demonstrate that NO causes peripheral analgesia via stimulation of GC and supports the suggestion that at this site morphine and acetylcholine analgesia is subsequent to NO release. In the mechanism of the central analgesic effect of morphine, the cGMP system is activated but via NO release, probably by a direct stimulation of the receptors. This is the first demonstration that links peripheral and central analgesic effect of morphine to the stimulation of GC system.
Department of Pharmacology, Faculty of Medicine of Ribeiräo Preto, Brasil.
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Duarte
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Lorenzetti
D000109:Acetylcholine / Q000494:pharmacology*; D000700:Analgesics; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D010147:Pain Measurement; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010793:Phthalazines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011930:Reaction Time / Q000187:drug effects; D019323:omega-N-Methylarginine
D000700:Analgesics; D010726:Phosphodiesterase Inhibitors; D010793:Phthalazines; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D009020:Morphine; D001120:Arginine; D006162:Guanylate Cyclase; C052490:MY 5445; D000109:Acetylcholine