Antagonism of Nitrous Oxide Antinociception in Mice by Intrathecally Administered Antisera to Endogenous Opioid Peptides

Abstract

Previously it was demonstrated that nitrous oxide antinociception in the mouse abdominal constriction test is mediated by κ-opioid receptors. Since nitrous oxide is thought to cause the neuronal release of endogenous opioid peptide to stimulate opioid receptors, this study was designed to identify the opioid peptides involved, especially in the spinal cord, by determining whether nitrous oxide antinociception can be differentially inhibited by intrathecally (i.t.) administered antisera to different opioid peptides. Male NIH Swiss mice were pretreated i.t. with rabbit antisera to opioid peptides then exposed 24 h later to one of three different concentrations of nitrous oxide in oxygen. Dose-response curves constructed from the data indicated that the antinociceptive effect of nitrous oxide was significantly antagonized by antisera to various dynorphins (DYNs) and methionine-enkephalin (ME), but not by antiserum to β-endorphin (β-EP). The AD₅₀ values for nitrous oxide antinociception were significantly elevated by antisera to DYNs and ME but not β-EP. These findings of this study support the hypothesis that nitrous oxide antinociception in the mouse abdominal constriction test involves the neuronal release of DYN and ME in the spinal cord.

Nitrous oxide-antinociception is mediated by opioid receptors and nitric oxide in the periaqueductal gray region of the midbrain

“…Since we have proposed in earlier investigations that N 2 O owes its antinociceptive effect in animals to stimulated neuronal release of endogenous opioid peptides (Branda et al, 2000;Cahill et al, 2000), the importance of the present findings is the localization of both opioid and NO mechanisms in the PAG of the midbrain. In as much as inhibition of NOS can significantly attenuate the increase in release of methionine-enkephalin in the rat spinal cord in response to centrally-administered β-endorphin (Hara et al, 1995), one explanation of these findings is that NO may play a key regulatory role in the N 2 O-stimulated neuronal release of endogenous opioid peptides that then activate opioid receptors in the PAG.…”

Role of Nitric-Oxide Synthase Isoforms in Nitrous Oxide Antinociception in Mice

“…N 2 O must, therefore, activate a mechanism or cascade that continues to its ultimate conclusion (antinociception) despite termination of exposure and the rapid elimination of N 2 O from the body in the expired air. That central mechanism is hypothesized to be the stimulated neuronal release of dynorphin with subsequent activation of central -opioid receptors (Branda et al, 2000;Cahill et al, 2000). The N 2 O-induced antinociceptive effect was dose dependently antagonized by SMTC and L-NIO but not AMT.…”

“…and i.t. pretreatment with rabbit antisera against rat dynorphin (Branda et al, 2000;Cahill et al, 2000).…”

Combination of inhaled nitrous oxide and oral opioids induces long-lasting analgesic effects in patients with neuropathic pain: ProtoTOP study post hoc exploratory analyses

“…14,35 The analgesic effects are also blocked by lesioning 37 of or after microinjections of opioid antagonists in the periaqueductal gray (PAG), 18,22 indicating that, similar to opiates, N 2 O acts in the PAG, whose role in pain modulation is well established. This action consists of the release of endogenous kappa ligands such as dynorphins 11 that, through inhibition of GABAergic neurons, disinhibit catecholaminergic pain descending modulatory systems. 5,16,17 Some data also suggested the role of nociceptine in these mechanisms.…”

“…These pronociceptive NMDA-dependent mechanisms are activated in parallel with the antinociceptive mechanisms and may decrease analgesic effects and lead to the development of hyperalgesia. 11,13,23 Of interest, similar to other NMDA receptor antagonists, N 2 O can strongly inhibit these phenomena in both animals 7,30 and humans. 15,34 On the basis of these experimental data suggesting that the combination of N 2 O and opiates could result in additive or even multiplicative analgesic effects, we hypothesized that the effects of N 2 O/O 2 mixture inhalation in patients with neuropathic pain would be larger in patients receiving opioids as a concomitant treatment.…”