κ-Opioid receptor mediates the antinociceptive effect of nitrous oxide in mice

Background Our previous reports demonstrated that genetic deletion of μ-opioid receptor has no influence on the anaesthetic and antinociceptive effects of nitrous oxide (N 2 O) in mice, and that an antagonist selective for κ-opioid receptor (KOP), but not that selective for δ-opioid receptor, suppresses the antinociceptive effect of N 2 O. However, it is not known whether genetic deletion of KOP affects the N 2 O actions. Methods We measured the minimum alveolar concentration (MAC) of volatile anaesthetics in the absence and presence of N 2 O. The antinociceptive action of N 2 O was tested by an acetic acid-writhing test and a hot-plate test. The number of c-Fos-immunopositive cells in sections from the lumbar spinal cord was counted to test whether the descending inhibitory system participates in the pharmacological action of N 2 O. The hypnotic action of N 2 O was assessed by measuring the N 2 O-induced decrease in the EC 50 for loss of the righting reflex (EC 50 -LORR) of sevoflurane. Results Sevoflurane MAC was not significantly reduced by N 2 O and its antinociceptive action was almost completely abolished in KOP-knockout (KO) mice. The N 2 O-induced increase in c-Fos-immunopositive cells in laminae III–IV of the lumbar spinal cord was significant in wild-type (WT), but not in KOP-KO mice. In contrast, sevoflurane EC 50 -LORR was similarly reduced by N 2 O in WT and KOP-KO mice. Conclusions Our study suggests that N 2 O demonstrates its antinociceptive action and reduces sevoflurane MAC in mice through KOP activation, whereas its hypnotic potency is not dependent on KOP activation.