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

The effect of the δ-selective agonist [D-Pen²,D-Pen⁵]enkephalin (DPDPE) on the antinociception produced by intracerebroventricular (i.c.v.) administration of the μ agonists morphine, [D-Ala², NMePhe⁴,Gly-ol⁵]enkephalin (DAGO), [NMePhe³,D-Pro⁴]morphiceptin (PLO17), β-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 δ-selective antagonist ICII74,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH) (where Aib is α-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 β-endorphin antinociception. The results of the present study provide support for the hypothesis that the enkephalins may function to modulate antinociception produced at the μ receptor; such modulation may come about via the existence of an opioid μ-δ receptor complex. The μ receptors existing in such a complex may be selectively activated by morphine and normorphine, but not the other μ agonists studied here. Thus, the enkephalins may function both to directly initiate, as well as to modulate, some forms of supraspinal μ receptor-mediated antinociception.