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Vol. 299, Issue 3, 1120-1125, December 2001

Acute Antinociceptive Tolerance and Asymmetric Cross-Tolerance between Endomorphin-1 and Endomorphin-2 Given Intracerebroventricularly in the Mouse

Hsiang-en Wu, Kuei-chun Hung, Hirokazu Mizoguchi, James M. Fujimoto and Leon F. Tseng

Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin

Development of tolerance in mice pretreated intracerebroventricularly with µ-opioid receptor agonist endomorphin-1, endomorphin-2, or [D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin (DAMGO) was compared between endomorphin-1- and endomorphin-2-induced antinociception with the tail-flick test. A 2-h pretreatment with endomorphin-1 (30 nmol) produced a 3-fold shift to the right in the dose-response curve for endomorphin-1. Similarly, a 1-h pretreatment with endomorphin-2 (70 nmol) caused a 3.9-fold shift to the right for endomorphin-2. In cross-tolerance experiments, pretreatment with endomorphin-2 (70 nmol) caused a 2.3-fold shift of the dose-response curve for endomorphin-1, whereas pretreatment with endomorphin-1 (30 nmol) caused no change of the endomorphin-2 dose-response curve. Thus, mice acutely tolerant to endomorphin-1 were not cross-tolerant to endomorphin-2, although mice made tolerant to endomorphin-2 were partially cross-tolerant to endomorphin-1; an asymmetric cross-tolerance occurred. Pretreatment with DAMGO 3 h before intracerebroventricular injection of endomorphin-1, endomorphin-2, or DAMGO attenuated markedly the antinociception induced by endomorphin-1 and DAMGO but not endomorphin-2. It is proposed that two separate subtypes of µ-opioid receptors are involved in antinociceptive effects induced by endomorphin-1 and endomorphin-2. One subtype of opioid µ-receptors is stimulated by DAMGO, endomorphin-1, and endomorphin-2, and another subtype of µ-opioidreceptors is stimulated solely by endomorphin-2.

0022-3565/01/2993-1120$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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