Mediation of swim-stress antinociception by the opioid delta₂ receptor in the mouse

The present study has characterized the antinociceptive response to cold water swim-stress (CWSS) in mice using opioid-selective antagonists as well as tolerance and cross-tolerance approaches. Mice subjected to CWSS using water at 5°C for 3 min showed a marked antinociceptive response in the tail- flick test, which reached approximately 90% after +10 min, and which persisted for 15 to 20 min. This antinociceptive response (at +10 min) was antagonized by naloxone or by the δ antagonist ICI 174,864. Additionally, the CWSS response was antagonized by the opioid δ₂ antagonist, naltrindole- 5'-isothiocyanate, but not by the δ₁ antagonist, [D- Ala²,Leu⁵,Cys⁶]enkephalin, or by the μ antagonist, β-funaltrexamine or by the κ antagonist, norbinaltorphimine. Although the CWSS-induced antinociceptive effect was blocked by some δ antagonists and tolerance resulted from the CWSS-induced response, the decrease in body temperature after each CWSS exposure was not affected by the opioid antagonists and reliably occurred in CWSS-tolerant mice, suggesting that the observed antinociception was independent of changes in body temperature. In mice rendered tolerant to the antinociceptive actions of the μ agonist, [D- Ala²,NMPhe⁴,Gly-ol]enkephalin, or to [D-Pen²,D-Pen⁵]enkephalin (predominantly a δ₁ agonist), the CWSS-induced antinociceptive response was unaltered. In contrast, in mice tolerant to the δ₂ agonist, [D- Ala²,Glu⁴]deltorphin, the CWSS-induced antinociceptive response was markedly and significantly reduced. Repeated exposure to CWSS over 3 days resulted in tolerance to the CWSS-induced antinociceptive effect; in CWSS- tolerant mice, no cross-tolerance was observed to [D-Ala²,NMPhe⁴,Gly- ol]enkephalin or to [D-Pen²,D-Pen⁵]enkephalin, but significant cross- tolerance occurred to the antinociceptive effects of [D- Ala²,Glu⁴]deltorphin. Thus, on the basis of 1) selective antagonism by the δ₂ antagonist, naltrindole-5'-isothiocyanate; 2) lack of antagonism of the CWSS-induced response by the δ₁ antagonist, [D- Ala²,Leu⁵,Cys⁶]enkephalin, the μ antagonist, β-funaltrexamine or the κ antagonist, norbinaltorphimine; 3) selective and two-way antinociceptive cross-tolerance between the δ₂ agonist, [D-Ala²,Glu⁴]deltorphin, and CWSS; and 4) a two-way lack of cross-tolerance between [D-Pen²,D- Pen⁵]enkephalin or [D-Ala²,NMPhe⁴,Gly-ol]enkephalin and CWSS-induced antinociception, it is suggested that the antinociceptive response to CWSS involves the activation of endogenous opioid systems at the opioid δ₂ receptor.