Nitrous Oxide: Mechanism of Its Antinociceptive Action

Nitrous oxide (N₂O) is an anesthetic gas known to produce an analgesic effect at sub-anesthetic concentrations. This analgesic property of N₂O can be clinically exploited in a broad range of conditions where pain relief is indicated. The mechanism of this analgesic effect was long thought to be nonspecific in nature, but a landmark study by Berkowitz and others in 1976 first implicated an opioid mechanism of action, possibly via N₂O-stimulated neuronal release of endogenous opioid peptides to activate opioid receptors. N₂O-induced release of opioid peptide has been demonstrated in both in vivo and in vitro preparations. Reversal of N₂O-induced antinociception in animals by narcotic antagonists has been reported by a number of laboratories. Subsequent studies have utilized more selective opioid antagonists to identify the opioid receptor subtypes involved in the antinociceptive effect of N₂O. Extensive pharmacological testing in the mouse abdominal constriction and rat hot plate paradigms have established that N₂O-induced antinociception is mediated by κ-opioid receptors in the former and by µ- and -opioid receptors in the latter. Current studies focus on two recent developments. The poor responsiveness of the DBA/2J mouse strain to N₂O has led to pharmacogenetic studies that hope to identify the underlying genetic basis for antinociceptive responsiveness to N₂O. Other research suggests an involvement of nitric oxide (NO) in mediating the antinociceptive effects of N₂O in both rats and mice.