The effects of various mu and kappa opioid agonists were evaluated in three squirrel monkeys responding under a fixed-ratio 30 schedule of food presentation before, during and after a regimen of chronic morphine administration. Initially, dose-effect curves for the mu opioid agonists morphine and l-methadone, the kappa opioid agonists U50,488 and tifluadom, the mixed mu/kappa opioid agonist ethylketocyclazocine, and the non-opioid compound pentobarbital were determined in non-tolerant squirrel monkeys. Subsequently, monkeys were administered up to 3.0 mg/kg of morphine twice daily for 8-9 weeks, which resulted in a 1/2 to 3/4 log unit shift to the right of the morphine dose-effect curve relative to its prechronic position. During the chronic morphine regimen, the l-methadone dose-effect curve shifted to the right approximately 3/4 log unit, while the U50,488 and pentobarbital dose-effect curves did not change. In contrast, the ethylketocyclazocine and tifluadom dose-effect curves shifted to the left approximately 1/4 and 3/4 log unit, respectively. The lack of cross-tolerance between mu and kappa agonists in morphine-tolerant squirrel monkeys observed in the present study provides further support for the differentiation of mu and kappa agonists. The occurrence of leftward shifts in the dose-effect curves of some opioid compounds with kappa agonist activity during the regimen of chronic morphine administration suggests that morphine tolerance modulates their