Modulation of [mu]-mediated antinociception by [delta] agonists in the mouse: selective potentiation of morphine and normorphine by [D-Pen2, D-Pen5]enkephalin

Abstract

The effect of the [delta]-selective agonist [D-Pen2,D-Pen5]enkephalin (DPDPE) on the antinociception produced by intracerebroventricular (i.c.v.) administration of the [mu] agonists morphine, [D-Ala2, NMePhe4,Gly-ol5]enkephalin (DAGO), [NMePhe3,D-Pro4]morphiceptin (PLO17), [beta]-endorphin, phenazocine, etorphine and sufentanil was studied in mice. Only the antinociceptive effects of morphine and normorphine were modulated by i.c.v. coadministration of a dose of DPDPE which did not prodice any significant antinociception alone. Both the morphine and normorphine dose-response lines were displaced to the left in the presence of DPDPE. The [delta]-selective antagonist ICII74,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH) (where Aib is [alpha]-aminoisobutyric acid) blocked the modulation of morphine antinociception by DPDPE. ICI 174,864 alone failed to produce either a significant increase or decrease of morphine, phenazocine, etorphine or [beta]-endorphin antinociception. The results of the present study provide support for the hypothesis that the enkephalins may function to modulate antinociception produced at the [mu] receptor; such modulation may come about via the existence of an opioid [mu]-[delta] receptor complex. The [mu] receptors existing in such a complex may be selectively activated by morphine and normorphine, but not the other [mu] agonists studied here. Thus, the enkephalins may function both to directly initiate, as well as to modulate, some forms of supraspinal [mu] receptor-mediated antinociception.