Cross-tolerance between the different mu-opioid receptor agonists endomorphin-1, endomorphin-2 and morphine at the spinal level in the rat.

In the present study we investigated the development of tolerance to an antinociceptive effect after intrathecal administration of endomorphin-1, endomorphin-2 and morphine in tail-flick and paw pressure tests. We also assessed cross-tolerance between the antinociceptive effects of the two endogenous mu-opioid receptor agonists - endomorphins and morphine. The tolerance developed on day 3 after i.th. injection of both endomorphins, endomorphin-2 (18, 36 nmol), endomorphin-1 (16 nmol). After morphine (30 nmol) the tolerance developed on day 6. Our study described the cross-tolerance between morphine and endomorphin-1, but not endomorphin-2. In comparison with naive rats, morphine had a weaker antinociceptive effect in rats tolerant to endomorphin-1. In contrast, no cross-tolerance was observed after administration of endomorphin-2 in rats tolerant to endomorphin-1. In rats tolerant to endomorphin-2, the antinociceptive effect of morphine and endomorphin-1 was attenuated in both the tests used. Our results suggest that the three ligands of mu-opioid receptors probably act via different subtypes of the mu-opioid receptor.