Antinociceptive Response to Nitrous Oxide Is Mediated by Supraspinal Opiate and Spinal α2 Adrenergic Receptors in the Rat

Background : Despite nearly 150 years of clinical use, the mechanism(s) of action of nitrous oxide (N 2 O) remains in doubt. In some but not all studies the analgesic properties of N 2 O can be attenuated by opiate receptor antagonists. The purported mechanism for the opiate antagonistic effect relates to the finding that N 2 O increases supraspinal levels of endogenous opiates, although this finding has been disputed. Based on the observations that (1) N 2 O promotes the release of catecholamines, including the endogenous α 2 adrenergic agonist norepinephrine, and (2) that descending noradrenergic inhibitory pathways are activated by opioid analgesics, this study sought to determine whether α 2 adrenergic receptors are involved in the antinociceptive action of nitrous oxide. Methods : Institutional approval was obtained for the study. Rats breathed 70% N 2 O and 30% O 2 in an enclosed chamber. After a 30-min exposure, significant antinociception was indicated by an increase in the latency response to a noxious stimulus (tail-flick latency). The tail-flick latency was tested in rats exposed to 70% N 2 O after either systemic or regional (intrathecal or intracerebroventricular) injections with either competitive (atipamezole ; yohimbine) or noncompetitive (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) α 2 adrenoceptor antagonists, or the opiate receptor antagonist naloxone. Results : When administered systemically, both the opiate (naloxone) and α 2 adrenoceptor antagonists (atipamezole, yohimbine, and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) blocked the enhanced tail-flick latency response to N 2 O. Naloxone administered intracerebroventricularly, but not intrathecally, blocked the enhanced tail-flick latency response to N 2 O. Conversely, atipamezole administered intrathecally, but not intracerebroventricularly, blocked the enhanced tail-flick latency response to N 2 O. Conclusions : These data suggest that both supraspinal opiate and spinal α 2 adrenoceptors play a mediating role in the antinociceptive response to N 2 O in rats. A possible mechanism may involve a descending inhibitory noradrenergic pathway that may be activated by opiate receptors in the periaqueductal gray region of the brain stem in the rat after exposure to N 2 O.