Nitrous oxide produces antinociceptive response via α2B and/or α2C adrenoceptor subtypes in mice

Background Opiate receptors in the periaqueductal gray region and alpha(2) 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 alpha(2) 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 alpha(2A) adrenoceptor using tail-flick latency. The antinociceptive effect of N2O was tested after pretreatment systemically with yohimbine (nonselective alpha(2) antagonist), naloxone (opiate antagonist), L659,066 (peripheral alpha(2)-antagonist) and prazosin (alpha(2B)- and alpha(2C)- selective antagonist). The tail-flick latency to dexmedetomidine (D-med), a nonselective alpha(2) 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 alpha(2B)-/alpha(2C)-receptor antagonists but not by a central nervous system-impermeant alpha(2) antagonist (L659,066). Whereas dexmedetomidine exhibited no antinociceptive response in the D73N mice, the robust antinociceptive response in the wild-type Lifter mates could not be blocked by a selective alpha(2B)-/alpha(2C)-receptor antagonist. Conclusion: These data confirm that the antinociceptive response to an exogenous alpha(2)-agonist is mediated by an alpha(2A) adrenoceptor and that there appears to be a role for the alpha(2B)- or alpha(2C)-adrenoceptor subtypes, or both, in the analgesic response to N2O.