Differential cross-tolerance to opioids in squirrel monkeys responding under a shock titration schedule

The opioid agonists morphine, l-methadone, ethylketazocine, U50,488 and bremazocine were examined in squirrel monkeys responding under a schedule of shock titration before, during and after chronic morphine administration. Before chronic morphine administration, all drugs produced dose-dependent increases in median shock level (the intensity below which monkeys maintained shock 50% of the time). After approximately 6 weeks of daily morphine administration, dose-effect curves for the mu agonist morphine shifted to the right approximately 3/4 log unit. Dose-effect curves for the mu agonist l-methadone also shifted to the right, approximately 1/4 log unit. In contrast, dose-effect curves for the kappa agonist ethylketazocine did not shift during chronic morphine administration, whereas those for the kappa agonists U50,488 and bremazocine shifted to the left approximately 1/2 log unit. After termination of daily morphine administration, dose-effect curves returned toward their prechronic positions. The present study demonstrates that repeated administration of morphine produces tolerance to its antinociceptive effects, as well as cross-tolerance selective to other opioids possessing mu agonist properties. Morphine tolerance may be a useful procedure not only for distinguishing mu from kappa opioid antinociceptive activity in the squirrel monkey, but also for differentiating among kappa opioids that have varying degrees of mu agonist and antagonist activity.