Bhargava H N, Gulati A
Department of Pharmacodynamics (m/c 865), University of Illinois, Chicago 60612.
Eur J Pharmacol. 1990 Nov 13;190(3):305-11. doi: 10.1016/0014-2999(90)94194-3.
The effect of chronic administration of morphine and its withdrawal on the characteristics of mu-opiate receptors was determined in male Sprague-Dawley rats. The ligand used for characterizing the receptors was [3H][D-Ala2,MePhe4,Gly5-ol]enkephalin ([3H]DAMGO). Rats were implanted s.c. under light ether anesthesia with six morphine pellets (each containing 75 mg of morphine free base). Rats serving as controls were implanted similarly with placebo pellets. Two sets of animals were used. In one group of rats, the pellets were left intact (tolerant-dependent) at the time of killing and in the other the pellets had been removed 18 h earlier (abstinent). The spinal cord and brain regions (amygdala, hippocampus, hypothalamus, corpus striatum, midbrain, pons and medulla, and cortex) were dissected. In morphine-abstinent rats, the binding of ligands of mu-opiate receptors to membranes of spinal cord and brain regions did not change. In non-abstinent morphine-tolerant-dependent rats, the binding of [3H]DAMGO to membranes of spinal cord, pons and medulla, and cerebral cortex was found to be decreased. These changes were due to decreases in the Bmax values rather than Kd values for the binding of [3H]DAMGO. The results clearly indicate that morphine-induced tolerance-dependence in the rat is associated with changes in the selected brain regions and spinal cord with mu-opiate receptors being down-regulated in spinal cord, pons and medulla, and cerebral cortex. It is concluded that tolerance to morphine in the rats may be due to down-regulation of central mu-opiate receptors. However, mu-opiate receptors are unaffected in morphine abstinence.
在雄性斯普拉格 - 道利大鼠中测定了长期给予吗啡及其戒断对μ - 阿片受体特性的影响。用于表征受体的配体是[3H][D - Ala2，MePhe4，Gly5 - ol]脑啡肽（[3H]DAMGO）。在轻度乙醚麻醉下，给大鼠皮下植入六粒吗啡丸（每粒含75mg吗啡游离碱）。作为对照的大鼠同样植入安慰剂丸。使用两组动物。一组大鼠在处死时丸剂保持完整（耐受 - 依赖组），另一组大鼠在处死前18小时取出丸剂（戒断组）。解剖脊髓和脑区（杏仁核、海马体、下丘脑、纹状体、中脑、脑桥和延髓以及皮层）。在吗啡戒断的大鼠中，μ - 阿片受体配体与脊髓和脑区膜的结合没有变化。在未戒断的吗啡耐受 - 依赖大鼠中，发现[3H]DAMGO与脊髓、脑桥和延髓以及大脑皮层膜的结合减少。这些变化是由于[3H]DAMGO结合的Bmax值降低而不是Kd值降低所致。结果清楚地表明，大鼠中吗啡诱导的耐受 - 依赖与所选脑区和脊髓的变化有关，脊髓、脑桥和延髓以及大脑皮层中的μ - 阿片受体下调。得出的结论是，大鼠对吗啡的耐受性可能是由于中枢μ - 阿片受体下调所致。然而，μ - 阿片受体在吗啡戒断时未受影响。
