Antagonism of the Antinociceptive Effect of Nitrous Oxide by Inhibition of Enzyme Activity or Expression of Neuronal Nitric Oxide Synthase in the Mouse Brain and Spinal Cord

摘要

Previous studies have implicated nitric oxide (NO) in the antinociceptive response to the anesthetic gas nitrous oxide (N2O). The present study was conducted to confirm this NO involvement using pharmacological and gene knockdown and knockout strategies to inhibit the supraspinal and spinal production of NO. Antinociceptive responsiveness to 70% N2O was assessed using the acetic acid (0.6%) abdominal constriction test in NIH Swiss mice following intracerebroventricular (i.c.v.) or intrathecal (i.t.) pretreatment with the NOS-inhibitor L-N^G-nitro arginine methyl ester (L-NAME) or an antisense oligodeoxynucleotide (AS-ODN) directed against neuronal NOS (nNOS). Experiments were also conducted in mice homozygous for a defective nNOS gene (nNOS^−/−). Mice that were pretreated i.c.v. or i.t. with L-NAME (1.0 μg) both exhibited 80-90% reduction in the magnitude of the N2O-induced antinociceptive response. Mice that were pretreated i.c.v. or i.t. with nNOS AS-ODN (3×25 μg) exhibited a 60-80% antagonism of the antinociceptive response. Compared to wild-type mice, nNOS knockout mice showed a 60% reduction in N2O-induced antinociception. These findings consistently demonstrate that transient or developmental suppression of nNOS expression significantly reduces antinociceptive responsiveness to N2O. NO of both supraspinal and spinal origin, therefore, plays an important role in the antinociceptive response to N2O.