L-NAME causes antinociception by stimulation of the arginine-NO-cGMP pathway

N-G-NITRO-L-ARGININE methyl ester (L-NAME) has been used extensively as a p aradigmatic inhibitor of NO synthase and has been shown to cause antinocice ption in several experimental models. We describe here how L-NAME produced a dose-dependent antinociceptive effect when injected intraperitoneally in the mouse after acetic acid induced writhings, or intraplantarly in the rat paw pressure hyperalgesia induced by carrageenin or prostaglandin E2. In c ontrast another NO synthase inhibitor, N-G-monomethyl-L-arginine (L-NMMA), had no significant effect per se but inhibited L-NAME systemic induced anti nociception in mice and local induced antinociception in the rat paw hypera lgesia test. D-NAME had no antinociceptive effect upon carrageenin-induced hyperalgesia. Pretreatment of the paws with two inhibitors of guanylate cyc lase, methylene blue (MB) and 1H-:[1,2,4]-oxadiazolo-:[4,3-a] quinoxalin-1- one (ODQ) abolished the antinociceptive effect of L-NAME. L-Arginine and th e cGMP phosphodiesterase inhibitor, MY 5445 significantly enhanced the L-NA ME antinociceptive effect. The central antinociceptive effect of L-NAME was blocked by co- administration of L-NMMA, ODQ and MB. The present series of experiments shows that L-NAME, but not L-NMMA, has an antinociceptive effe ct. It can be suggested that L-NAME causes the antinociceptive effect by st imulation of the arginine/ NO/ cGMP pathway, since the antinociceptive effe ct of L-NAME can be antagonized by L-NMMA and abolished by the guanylate cy clase inhibitors (MB and ODQ), In addition, the NO synthase substrate, L-ar ginine and the cGMP phosphodiesterase inhibitor, MY5445 were seen to potent iate the effects of L-NAME. Thus, L-NAME used alone, has limitations as a s pecific inhibitor of the arginine-NO-cGMP pathway and may therefore be a po or pharmacological tool for use in characterising participation in pathophy siologlcal processes.