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

Todd W Vanderah, K. D. Wild, A. E. Takemori, M. Sultana, P. S. Portoghese, W. D. Bowen, H. I. Mosberg, Frank 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
Publication statusPublished - 1992


ASJC Scopus subject areas

  • Pharmacology

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