Role of nitric-oxide synthase isoforms in nitrous oxide antinociception in mice

Exposure of mice to the anesthetic gas N2O evokes a prominent antinociceptive effect that is sensitive to antagonism by nonselective nitric-oxide synthase (NOS) inhibitors. The present study was conducted to identify whether a specific NOS isoform is implicated in N2O antinociception in mice. In the abdominal constriction test, exposure of mice to 25, 50, and 70% N2O resulted in a concentration-dependent antinociceptive effect that persisted for up to 6 min following removal of the mice from the N2O atmosphere into room air. This N2O antinociceptive effect was antagonized by pretreatment with S-methyl-l-thiocitrulline (SMTC) and higher doses of l-N5-(1-iminoethyl)-ornithine (l-NIO), which reportedly inhibit the neuronal and endothelial isoforms of NOS, respectively. Nevertheless, the N2O-induced antinociception was unaffected by pretreatment with low doses of either SMTC or l-NIO or by pretreatment with 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), which selectively inhibits inducible NOS. The s.c. pretreatment with SMTC and l-NIO reduced brain NOS activity in a dose-dependent manner, whereas AMT had no such effect. Moreover, in blood pressure experiments, SMTC increased SBP in dose-unrelated fashion, whereas l-NIO showed an appreciably weaker but dose-related increase in SBP. The i.c.v. pretreatment with SMTC also reduced N2O antinociception and brain NOS activity without increasing of SBP. These results suggest that it is the neuronal isoform of NOS that is involved in mediation of the antinociceptive effect of N2O in the mice.