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

T. W. Vanderah, K. D. Wild, A. E. Takemori, M. Sultana, P. S. Portoghese, W. D. Bowen, H. I. Mosberg, F. Porreca

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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.

Original languageEnglish (US)
Pages (from-to)190-197
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - 1992


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