MORPHINE ANTAGONIZES U50,488S EFFECTS IN A SQUIRREL-MONKEY SHOCK TITRATION PROCEDURE

To determine whether a mu opioid agonist modulates the effects of a ka ppa opioid agonist in squirrel monkeys responding under a shock titrat ion procedure, morphine was administered in combination with an ED7, d ose of U50,488. Morphine (0.03-0.3 mg/kg) did not alter U50,488's earl y peak effects (15-25 min post-injection), but dose dependently antago nized 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 t he right. After 6-8 weeks of daily morphine administration, higher dos es 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 pe ak 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 ka ppa receptors, morphine's kappa antagonist activity is limited by its mu agonist effects, particularly in the non-morphine-tolerant monkey.