d-Pro²-Endomorphin-1 andd-Pro²-Endomorphin-2, Respectively, Attenuate the Antinociception Induced by Endomorphin-1 and Endomorphin-2 Given Intrathecally in the Mouse

Abstract

First, the antinociception with the tail-flick test ofd-Pro²-endomorphin-1 andd-Pro²-endomorphin-2 given i.t. was compared with that produced by endomorphin-1 and -2 in male CD-1 mice. High doses of d-Pro²-endomorphin-1 (0.2–0.4 pmol) and d-Pro²-endomorphin-2 (300–800 pmol) given i.t. produced antinociception with low intrinsic activity [about 25% maximum possible effect (MPE)] compared with that of endomorphin-1 (16.4 nmol) and endomorphin-2 (35 nmol) (>90% MPE). Second, coadministration of a low dose ofd-Pro²-endomorphin-1 (0.1 pmol), which given alone did not affect the tail-flick latencies, markedly attenuated the antinociception induced by endomorphin-1 (16.4 nmol) but not by endomorphin-2 (35 nmol). Similarly, coadministration of a low dose ofd-Pro²-endomorphin-2 (200 pmol), which given alone did not affect the tail-flick latencies, significantly attenuated the antinociception induced by endomorphin-2 (35 nmol) and, to a much lesser extent, endomorphin-1 (16.4 nmol). It is concluded thatd-Pro²-endomorphin-1 andd-Pro²-endomorphin-2 at high doses were partial opioid receptor agonists to produce antinociception, and at low doses were opioid receptor antagonists to block selectively the antinociception induced by endomorphin-1 and endomorphin-2, respectively. Furthermore, our results are consistent with the view that the antinociception induced by endomorphin-1 and endomorphin-2 is mediated by the stimulation of different subtypes of μ-opioid receptors.