Antagonism of nitrous oxide antinociception in the rat hot plate test by site-specific mu and epsilon opioid receptor blockade.

The analgesic property of the anesthetic gas N2O has long been known and used to treat pain in clinical medicine and dentistry. The present study was conducted to identify by subtype and possible location the brain opioid receptors that mediate N2O antinociception in rats. A 5-min exposure to 70% N2O consistently evoked an antinociceptive effect in the hot plate test. This drug effect was partly antagonized in dose-related fashion by i.c.v. pretreatment with naltrexone, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 and beta-endorphin, which block multiple, mu and epsilon opioid receptors, respectively. However, the N2O-evoked antinociception was unaffected by i.c.v. pretreatment with either the delta opioid antagonist naltrindole or the kappa opioid antagonist nor-binaltorphimine. When D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 was administered intracerebrally directly into the periaqueductal gray, N2O antinociception was partly antagonized in a dose-dependent manner. The antinociceptive response to N2O was uninfluenced by beta-endorphin administered into the periaqueductal gray. The findings of these pharmacological antagonism studies are consistent with the hypothesis that exposure to N2O causes a neuronal release of beta-endorphin. These results indicate that supraspinal mu and epsilon opioid receptors mediate N2O antinociception in the rat hot plate paradigm and that one central site of such mu but not epsilon opioid receptors is the periaqueductal gray.