Craft R M, Dykstra L A
Department of Psychology, University of North Carolina, Chapel Hill.
J Pharmacol Exp Ther. 1990 Mar;252(3):945-52.
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.
在慢性吗啡给药前、给药期间和给药后，对松鼠猴在电击滴定程序下的反应进行了研究，观察了阿片类激动剂吗啡、左旋美沙酮、乙基酮佐辛、U50,488和布瑞马佐辛的作用。在慢性吗啡给药前，所有药物均使中位电击水平（猴子在该强度以下保持电击的时间占50%）产生剂量依赖性增加。在每日给予吗啡约6周后，μ激动剂吗啡的剂量-效应曲线向右移动约3/4对数单位。μ激动剂左旋美沙酮的剂量-效应曲线也向右移动，约1/4对数单位。相比之下，κ激动剂乙基酮佐辛的剂量-效应曲线在慢性吗啡给药期间未发生移动，而κ激动剂U50,488和布瑞马佐辛的剂量-效应曲线向左移动约1/2对数单位。在每日吗啡给药终止后，剂量-效应曲线恢复到给药前的位置。本研究表明，重复给予吗啡会产生对其镇痛作用的耐受性，以及对其他具有μ激动剂特性的阿片类药物的交叉耐受性。吗啡耐受性不仅可能是区分松鼠猴中μ和κ阿片类镇痛活性的有用方法，也是区分具有不同程度μ激动剂和拮抗剂活性的κ阿片类药物的有用方法。
