Involvement of the κ-opioid receptor in nitrous oxide-induced analgesia in mice

Abstract

Nitrous oxide (N(2)O)-induced analgesia is thought to be mediated by endogenous opioids. We previously showed that the mu-opioid receptor is not required for the analgesic action of N(2)O in mice using a gene knockout approach. In this study, we examined the effect of kappa- (KOP)- or delta-opioid receptor (DOP)-selective antagonists on N(2)O-induced analgesia. The analgesic effect of N(2)O was evaluated using a writhing test. Male C57BL/6 mice aged 7-8 weeks were assigned to control, N(2)O, KOP agonist, and DOP agonist groups. According to the group assignment, mice were pretreated with a KOP antagonist, nor-binaltorphimine (nor-BNI), a DOP antagonist, naltrindole hydrochloride (NTI), a KOP agonist U50488, and a DOP agonist SNC80. Mice in the control, KOP agonist, and DOP agonist groups were exposed to 25% oxygen/75% nitrogen for 30 min, and mice in the N(2)O group were exposed to 25% oxygen/75% N(2)O for 30 min. Nor-BNI [10 mg kg(-1), subcutaneously (s.c.)] significantly suppressed the analgesic effect of N(2)O and U50488. In contrast, NTI (10 mg kg(-1) s.c.) did not significantly affect the analgesic action of N(2)O, but almost completely inhibited the analgesic effect of SNC80. These results suggest that KOP plays an important role in the analgesic effect of N(2)O in mice.

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

“…The antinociceptive action of N 2 O was also almost completely abolished in KOP-KO mice, consistent with our previous reports showing that the antinociceptive action of N 2 O was not influenced by genetic deletion of MOP in mice 5 and that a KOP-selective antagonist suppressed the antinociceptive effect of N 2 O. 6 These results together indicate that KOP performs an important function in the antinociceptive action of N 2 O. N 2 O activates the noradrenergic descending inhibitory pathway and GABAergic interneurons in the spinal cord in rat. 21 We have shown that inhalation of 70% N 2 O significantly increases the number of c-Fos-immunopositive cells in laminae III-IV in WT and MOP-KO mice, which reflects activation of GABAergic interneurons by the noradrenergic descending inhibitory pathway in the mouse spinal cord.…”

“…3 However, it is unclear which of the naloxone-sensitive opioid receptors, including the m-, k-, and d-opioid receptors (MOP, KOP, and DOP, respectively), 4 is the most important in the pharmacological action of N 2 O. Our previous report demonstrated that the antinociceptive effect of N 2 O is not influenced by genetic deletion of MOP 5 and is significantly reduced by a KOP-selective antagonist, but unaffected by a DOP-selective antagonist, 6 suggesting that KOP is important in the antinociceptive action of N 2 O.…”

N-Methyl-d-Aspartate Receptor Channel Blocker–Like Discriminative Stimulus Effects of Nitrous Oxide Gas

“…The poor substitution produced by m-opioid agonist morphine is consistent with data showing that the opioid antagonist naloxone does not attenuate the subjective effects of 30% N 2 O in humans (Zacny et al, 1994(Zacny et al, , 1999. Likewise, the failure of the d-opioid agonist SNC-80 to substitute for N 2 O is consistent with reports that the d-opioid receptor agonist naltrindole does not attenuate N 2 O analgesia (Koyama and Fukuda, 2010). Our data showing that the selective k-opioid agonist U50-488H does not substitute for N 2 O is, however, in conflict with a previous study in which N 2 O generalized to the purported k-opioid agonist ethylketocyclazocine in guinea pigs trained to discriminate ethylketocyclazocine from vehicle (Hynes and Hymson, 1984).…”

“…The k-opioid antagonist nor-binaltorphimine but not the d-opioid antagonist naltrindole attenuates N 2 O analgesia (Koyama and Fukuda, 2010). A mixed agonist/antagonist at m-opioid receptors, b-chlornaltrexamine reverses N 2 O antinociceptive responses (Emmanouil et al, 2008).…”

Ketamine and nitrous oxide: The evolution of NMDA receptor antagonists as antidepressant agents

“…Nitrous oxide has effects on the endogenous opioid system that could contribute to analgesia and perhaps, to psychotropic effects [112][113][114][115]. Some evidence indicates that nitrous oxide exerts preferential effects on kappa-type opiate receptors over mu-type receptors [116,117]. Modulation of the opiate system may be important for antidepressant effects given recent evidence suggesting that an opiate receptor antagonist dampens the antidepressant effects of ketamine [80].…”