Vol. 303, Issue 2, 874-879, November 2002

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

Kuei-chun Hung, Hsiang-en Wu, Hirokazu Mizoguchi, Shinobu Sakurada, Toru Okayama, Tsutomu Fujimura, Kimie Murayama, Tsukasa Sakurada, James M. Fujimoto and Leon F. Tseng

Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin (K.-C.H., H.-E.W., H.M., J.M.F., L.F.T.); Department of Physiology and Anatomy, Tohoku Pharmaceutical University, Sendai, Japan (S.S.); Research Institute, Fuji Chemical Industries Ltd., Takaoka, Japan (T.O.); Central Laboratory of Medical Sciences, Juntendo University School of Medicine, Tokyo, Japan (T.F., K.M.); and Department of Biochemistry, Daiichi College of Pharmaceutical Science, Fukuoka, Japan (T.S.)

First, the antinociception with the tail-flick test of D-Pro²-endomorphin-1 and D-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 of D-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 of D-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 that D-Pro²-endomorphin-1 and D-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.