November 2002 Extramurally Speaking

CA Corresponding Author Te l/fax : (+55 ) 16 6232792 Email: shfe rre [email protected] N-NITRO-L-A RG ININE m ethyl este r (L-NAME) has been used ex tensive ly as a paradigm atic in h ibitor of NO synthase and has been show n to cause an tinociception in several ex perim ental m odels. We describe here how L-NAME produced a dose-dependen t an tinociceptive effect when in jected intraperitoneally in the m ouse after ace tic acid in duced w rith in gs , or in traplan tarly in th e rat paw pressure hyperalges ia in duced by carrageenin or prostaglandin E2. In con trast another NO synthase in hibitor, N-m onom ethyl-L-argin ine (L-NMMA), had no s ign ifican t effect per se but in h ibited L-NAME system ic induced an tinociception in m ice and local in duced an tinociception in the rat paw hyperalges ia test. D-NAME had no an tinociceptive e ffe ct upon carrageenin-in duced hyperalge s ia. Pre treatm ent of the paws w ith two in hibitor s of guanylate cyclas e, m ethylene blue (MB) and 1H-:[1,2,4]-ox adiazolo-:[4,3-a] quinox alin –1-one (ODQ) abolished the an tinociceptive effect of L-NAME. L-Argin in e and the cGMP phosphodies te rase in hibitor, MY 5445 s ignificantly enhanced the L-NAME antinociceptive effect. The cen tral an tinociceptive effe ct of L-NAME w as blocked by coadm in is tration of L-NMMA, ODQ and MB. The pre sen t serie s of ex per im ents show s that L-NAME, but not L-NMMA, has an an tinociceptive effect. It can be suggested that L-NAME cause s th e an tinociceptive effect by stim ulation of th e argin in e / NO/ cGMP pathway, s ince the an tinociceptive effect of L-NAME can be an tagonized by L-NMMA and abolished by the guanylate cyclase in hibitor s (MB and ODQ). In addition , th e NO synthase substrate, L-argin ine and the cGMP phosphodie steras e in hibitor, MY5445 were seen to poten tiate the effects of L-NAME. Th us, L-NAME used alone, has lim itations as a specific inh ibitor of the arginin e-NOcGMP pathw ay and m ay therefore be a poor pharm acological tool for use in characteris in g par ticipation in pathophysio logical proces ses .