Abstract

Administration of the anesthetic gas N2O evoked an antinociceptive effect in two rodent antinociception paradigms. In the mouse abdominal constriction test, pretreatment with the nitric oxide synthase (NOS) inhibitor L-NG-nitroarginine (L-NOARG) caused dose-related antagonism of the antinociceptive effect of N2O but not of either morphine or trans(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide methane sulfonate. This antinociceptive effect was also antagonized by systemic pretreatment with the NOS inhibitors L-NG-nitroarginine methyl ester (L-NAME) and L-NG-monomethylnitroarginine. The antagonism of N2O by L-NOARG and L-NAME was completely reversed by i.c.v. administration of L-arginine but not D-arginine. In the absence of NOS inhibition, N2O antinociception was potentiated by i.c.v. treatment with L-arginine but not D-arginine. The i.c.v. pretreatment with L-NAME also reduced N2O antinociception; this antagonism was also stereospecifically reversed by L-arginine. In the rat hot plate test, the antinociceptive response to 70% N2O was antagonized in dose-related manner by i.c.v. pretreatment with L-NOARG or L-NAME. N2O antinociception was restored by i.c.v. treatment with L-arginine but not D-arginine. However, neither L-arginine nor D-arginine alone affected N2O antinociception. These results implicate a key role for NO in the mediation of the antinociceptive effects of N2O in both mice and rats.