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NEUROPHARMACOLOGY

Role of Nitric-Oxide Synthase Isoforms in Nitrous Oxide Antinociception in Mice

Department of Pharmaceutical Sciences, College of Pharmacy (M.I., R.M.Q.) and Center for Integrative Biotechnology (R.M.Q.), Washington State University, Pullman, Washington; and Pharmacological Research Section (M.I.), Central Research Labs., SSP CO., LTD., Chiba, Japan

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.

Address correspondence to: Dr. Raymond M. Quock, Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, P.O. Box 646534, Pullman, WA 99164-6534. E-mail: quockr{at}wsu.edu

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