ANTINOCICEPTIVE RESPONSE TO NITROUS-OXIDE IS MEDIATED BY SUPRASPINAL OPIATE AND SPINAL ALPHA(2) ADRENERGIC-RECEPTORS IN THE RAT

Background: Despite nearly 150 years of clinical use, the mechanism(s) of action of nitrous oxide (N2O) remains in doubt. In some but not al l studies the analgesic properties of N2O can be attenuated by opiate receptor antagonists. The purported mechanism for the opiate antagonis tic effect relates to the finding that N2O increases supraspinal level s of endogenous opiates, although this finding has been disputed. Base d on the observations that (1) N2O promotes the release of catecholami nes, including the endogenous alpha(2) adrenergic agonist norepinephri ne, and (2) that descending noradrenergic inhibitory pathways are acti vated by opioid analgesics, this study sought to determine whether alp ha(2) adrenergic receptors are involved in the antinociceptive action of nitrous oxide. Methods: Institutional approval was obtained for the study. Rats breathed 70% N2O and 30% O-2 in an enclosed chamber. Afte r a 30-min exposure, significant antinociception was indicated by an i ncrease in the latency response to a noxious stimulus (tail-flick late ncy). The tail-flick latency was tested in rats exposed to 70% N2O aft er either systemic or regional (intrathecal or intracerebroventricular ) injections with either competitive (atipamezole; yohimbine) or nonco mpetitive (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) alpha(2) ad renoceptor antagonists, or the opiate receptor antagonist naloxone. Re sults: When administered systemically, both the opiate (naloxone) and (alpha(2) adrenoceptor antagonists (atipamezole, yohimbine, and N-etho xycarbonyl-2-ethoxy-1,2-dihydroquinoline) blocked the enhanced tail-fl ick latency response to N2O. Naloxone administered intracerebroventric ularly, but not intrathecally, blocked the enhanced tail-flick latency ) response to N2O. Conversely, atipamezole administered intrathecally, but not intracerebroventricularly, blocked the enhanced tail-flick la tency response to N2O. Conclusions: These data suggest that both supra spinal opiate and spinal alpha(2) adrenoceptors play a mediating role in the antinociceptive response to N2O in rats. A possible mechanism m ay involve a descending inhibitory noradrenergic pathway that may be a ctivated by opiate receptors in the periaqueductal gray region of the brain stem in the rat after exposure to N2O.