Modulation of morphine antinociception by swim-stress in the mouse: Involvement of supraspinal opioid delta-2 receptors

The present study evaluated the effect of a brief exposure of mice to cold-water swim-stress (CWSS) on the antinociceptive potency of i.c.v. given morphine. No significant antinociceptive response could be demonstrated in the warm-water tail-flick test, 10 min after a 30-sec exposure of mice to water at 5°C. However, the i.c.v. morphine dose-response curve in mice exposed to CWSS was displaced significantly to the left when compared to that obtained in control (i.e., non-CWSS-exposed) mice. Although coadministration of the delta antagonist, N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH 1 (ICI 174,864), with i.c.v. morphine did not produce antagonism of the antinociceptive action of this mu opiate, the leftward displacement of the i.c.v. morphine dose- response curve seen in CWSS-exposed mice was blocked in ICI 174,864-treated mice suggesting involvement of opioid delta receptors in the modulatory effect. Pretreatment of mice with the delta-1 antagonist, [D-Ala², Leu⁵, Cys⁶] enkephalin, did not antagonize the antinociception of morphine and further did not antagonize the leftward displacement produced by exposure to CWSS. Pretreatment of mice with the delta-2 antagonist, 5'-isothiocyanate, also did not antagonize the antinociceptive effects of morphine but blocked the leftward displacement in the morphine dose-response curve associated with CWSS, suggesting involvement of an opioid delta-2 receptor in this effect. Pretreatment of mice with the mu antagonist, β-funaltrexamine, produced a significant antagonism of the morphine antinociceptive effect as seen by a rightward displacement of the morphine dose-effect curve. Further, in these β-funaltrexamine-pretreated mice, exposure to CWSS did not result in an enhancement of morphine potency. Finally, i.c.v. pretreatment of mice with antibodies raised against [Leu⁵]enkephalin, but not antibodies against [Met⁵]enkephalin, blocked the modulatory action produced by exposure to CWSS; both antibodies to [Met⁵]enkephalin or [Leu⁵]enkephalin did not alter the morphine response directly. These data suggest that modulation of morphine potency by exposure to CWSS involves activation of an opioid delta- 2 receptor which may be functionally and/or physically associated with opioid mu receptors. Additionally, the modulatory action appears to be produced in the brain by release of a [Leu⁵]enkephalin-like molecule. Finally, these observations may provide, in part, a physiological basis for the observed increase in analgesic effectiveness of morphine in situations of stress.