Differential cross-tolerance to opioid agonists in morphine-tolerant squirrel monkeys responding under a schedule of food presentation

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The effects of various μ and ϰ 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. Initiallu, dose-effect curves for the μ opioid agonists morphine and l-methadone, the ϰ opioid agonists U50, 488 and tifluadom, the mixed μ/ϰ 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 1-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 μ and ϰ agonists in morphine-tolerant squirrel monkeys observed in the present study provides further support for the differentiation of μ and ϰ agonists. The occurrence of leftward shifts in the dose-effect curves of some opioid compounds with ϰ agonist activity during the regimen of chronic morphine administration suggests that morphine tolerance modulates their rate-decreasing effects.