Morphine antagonizes U50,488's effects in a squirrel monkey shock titration procedure.

To determine whether a mu opioid agonist modulates the effects of a kappa opioid agonist in squirrel monkeys responding under a shock titration procedure, morphine was administered in combination with an ED75 dose of U50,488. Morphine (0.03-0.3 mg/kg) did not alter U50,488's early peak effects (15-25 min post-injection), but dose dependently antagonized U50,488's later effects (40-100 min post-injection); these doses of morphine shifted the U50,488 dose-effect curve < 1/4 log unit to the right. After 6-8 weeks of daily morphine administration, higher doses of morphine (0.3-3.0 mg/kg) shifted the U50,488 dose-effect curve > 1/2 log unit to the right. Morphine still did not antagonize early peak effects of the ED75 dose of U50,488, but antagonized early and late effects of a lower dose. Thus, morphine is a weak kappa antagonist in the shock titration procedure. In addition to its low affinity for kappa receptors, morphine's kappa antagonist activity is limited by its mu agonist effects, particularly in the non-morphine-tolerant monkey.