Acute antinociceptive tolerance and asymmetric cross-tolerance between endomorphin-1 and endomorphin-2 given intracerebroventricularly in the mouse

Development of tolerance in mice pretreated intracerebroventricularly with mu -opioid receptor agonist endomorphin-1, endomorphin-2, or [D-Ala(2),N-Me -Phe(4),Gly-ol(5)]-enkephalin (DAMGO) was compared between endomorphin-1- a nd endomorphin-2-induced antinociception with the tail-flick test. A 2-h pr etreatment with endomorphin-1 (30 nmol) produced a 3-fold shift to the righ t in the dose-response curve for endomorphin-1. Similarly, a 1-h pretreatme nt with endomorphin-2 (70 nmol) caused a 3.9-fold shift to the right for en domorphin-2. In cross-tolerance experiments, pretreatment with endomorphin- 2 (70 nmol) caused a 2.3-fold shift of the dose-response curve for endomorp hin-1, whereas pretreatment with endomorphin-1 (30 nmol) caused no change o f the endomorphin-2 dose-response curve. Thus, mice acutely tolerant to end omorphin-1 were not cross-tolerant to endomorphin-2, although mice made tol erant to endomorphin-2 were partially cross-tolerant to endomorphin-1; an a symmetric cross-tolerance occurred. Pretreatment with DAMGO 3 h before intr acerebroventricular injection of endomorphin-1, endomorphin-2, or DAMGO att enuated markedly the antinociception induced by endomorphin-1 and DAMGO but not endomorphin-2. It is proposed that two separate subtypes of mu -opioid receptors are involved in antinociceptive effects induced by endomorphin-1 and endomorphin-2. One subtype of opioid mu -receptors is stimulated by DA MGO, endomorphin-1, and endomorphin-2, and another subtype of mu -opioid-re ceptors is stimulated solely by endomorphin-2.