Craft R M, Dykstra L A
Department of Psychology, University of North Carolina, Chapel Hill.
J Pharmacol Exp Ther. 1992 Jan;260(1):334-42.
The kappa opioid agonists U50,488, bremazocine, ethylketazocine and tifluadom and the opioid antagonist naltrexone were examined alone and in combination with morphine in a squirrel monkey shock titration procedure, before and during chronic morphine administration. Before chronic morphine administration (prechronic phase), all opioids except naltrexone produced dose-dependent increases in median shock level when administered alone. When combined with a dose of morphine that increased median shock level to 90% of maximum (ED90), naltrexone, U50,488 and bremazocine completely antagonized the effects of morphine in most monkeys, whereas ethylketazocine and tifluadom partially antagonized the effects of this dose of morphine. After 10 weeks of daily morphine administration (chronic phase), the average ED90 for morphine was increased 1 log unit. In contrast, average ED50 values for U50,488, bremazocine and tifluadom were decreaed 1/4 to 1/2 log unit, whereas the average ED50 for ethylketazocine did not change from the prechronic to chronic phases. When combined with morphine during the chronic phase, naltrexone completely antagonized the effects of the morphine ED90 at approximately the same doses as during the prechronic phase. In contrast, antagonist activity decreased for U50,488 and bremazocine, increased for ethylketazocine and did not change consistently for tifluadom, compared with the prechronic phase. The present study demonstrates that chronic morphine administration alters both the agonist and antagonist activity of kappa opioids. Changes in antagonist activity of kappa opioids after chronic morphine administration may be explained by concurrent changes in their agonist potency and the extent to which their agonist effects are mu-mediated.
在松鼠猴休克滴定程序中，于慢性吗啡给药之前和期间，对κ阿片受体激动剂U50,488、布瑞马唑辛、乙基酮唑辛和替氟朵以及阿片受体拮抗剂纳曲酮进行了单独检测，并检测了它们与吗啡联合使用的情况。在慢性吗啡给药之前（慢性前期），除纳曲酮外，所有阿片类药物单独给药时均产生剂量依赖性的中位休克水平升高。当与将中位休克水平提高到最大值的90%（ED90）的吗啡剂量联合使用时，纳曲酮、U50,488和布瑞马唑辛在大多数猴子中完全拮抗了吗啡的作用，而乙基酮唑辛和替氟朵部分拮抗了该剂量吗啡的作用。每日给予吗啡10周后（慢性期），吗啡的平均ED90增加了1个对数单位。相比之下，U50,488、布瑞马唑辛和替氟朵的平均ED50值降低了1/4至1/2个对数单位，而乙基酮唑辛的平均ED50从慢性前期到慢性期没有变化。在慢性期与吗啡联合使用时，纳曲酮在与慢性前期大致相同的剂量下完全拮抗了吗啡ED90的作用。相比之下，与慢性前期相比，U50,488和布瑞马唑辛的拮抗活性降低，乙基酮唑辛的拮抗活性增加，替氟朵的拮抗活性没有持续变化。本研究表明，慢性吗啡给药会改变κ阿片类药物的激动剂和拮抗剂活性。慢性吗啡给药后κ阿片类药物拮抗剂活性的变化可能是由于其激动剂效力的同时变化以及其激动剂作用由μ介导的程度所致。
