Nitrous oxide produces antinociceptive response via α(2B) and/or α(2C) adrenoceptor subtypes in mice

Background. Opiate receptors in the periaqueductal gray region and α₂ adrenoceptors in the spinal cord of the rat mediate the antinociceptive properties of nitrous oxide (N₂O). The availability of genetically altered mice facilitates the detection of the precise protein species involved in the transduction pathway. In this study, the authors establish the similarity between rats and mice in the antinociceptive action of N₂O and investigate which α₂ adrenoceptor subtypes mediate this response. Methods: After obtaining institutional approval, antinociceptive dose-response and time- course to N₂O was measured in wild-type and transgenic mice (D79N), with a nonfunctional α(2A) adrenoceptor using tail-flick latency. The antinociceptive effect of N₂O was tested after pretreatment systemically with yohimbine (nonselective α₂ antagonist), naloxone (opiate antagonist), L659,066 (peripheral α₂-antagonist) and prazosin (α(2B)- and α(2C)- selective antagonist). The tail-flick latency to dexmedetomidine (D-med), a nonselective α₂ agonist, was tested in wild-type and transgenic mice. Results: N₂O produced antinociception in both D79N transgenic and wild-type litter mates, although the response was less pronounced in the transgenic mice. Antinociception from N₂O decreased over time with continuing exposure, and the decrement was more pronounced in the transgenic mice. The antinociceptive response could be dose dependently antagonized by opiate receptor and selective α(2B)-/α(2C)-receptor antagonists but not by a central nervous system-impermeant α₂ antagonist (L659,066). Whereas dexmedetomidine exhibited no antinociceptive response in the D79N mice, the robust antinociceptive response in the wild-type litter mates could not be blocked by a selective α(2B)-/α(2C)-receptor antagonist. Conclusion. These data confirm that the antinociceptive response to an exogenous α₂-agonist is mediated by an α(2A) adrenoceptor and that there appears to be a role for the α(2B)- or α(2C)-adrenoceptor subtypes, or both, in the analgesic response to N₂O.