KAPPA-OPIATE AGONISTS INHIBIT ADENYLATE-CYCLASE AND PRODUCE HETEROLOGOUS DESENSITIZATION IN RAT SPINAL-CORD
KAPPA-OPIATE AGONISTS INHIBIT ADENYLATE-CYCLASE AND PRODUCE HETEROLOGOUS DESENSITIZATION IN RAT SPINAL-CORD
复制标题
DOI：
10.1111/j.1471-4159.1989.tb09130.x
复制
发表时间：
1989-02-01
影响因子：
4.7
通讯作者：
VOGEL, Z
中科院分区：
文献类型：
--
作者：
ATTALI, B;SAYA, D;VOGEL, Z
在大鼠脊髓中研究了急性和慢性激动剂暴露后阿片调节腺苷酸环化酶的性质。使用成年大鼠脊髓和脊髓-背根神经节共培养物的膜，我们发现：阿片受体与腺苷酸环化酶负偶联。《泰晤士报》-阿片激动剂（例如，U 50488）显著且剂量依赖性地抑制基础和毛喉素刺激的环化酶活性，而μ和δ激动剂无效。调节作用是立体特异性的，需要GTP的存在。质膜的EGTA处理消除了×-阿片受体激动剂对基础环化酶活性的抑制作用，并且这种抑制作用不能通过随后加入CA 2+来恢复。EGTA处理不影响时间。激动剂抑制毛喉素刺激的环化酶。结果还表明，在培养的细胞长期暴露于埃托啡或U 50488后，有× 10 - 6的损失。环化酶的激动剂抑制。此外，这种脱敏过程似乎是异源的，因为α 2-肾上腺素能激动剂（例如，可乐定或去甲肾上腺素）和毒蕈碱激动剂（卡巴胆碱）与未处理的培养物相比，表现出明显较低的抑制环化酶活性的效力。这种异源性脱敏的模式表明，长期暴露于.阿片类药物导致受体后调节成分的改变，可能是GTP结合蛋白。
The nature of the opiate modulation of adenylate cyclase following acute and chronic agonist exposure has been investigated in rat spinal cord. Using membranes of both adult rat spinal cord and spinal cord-dorsal root ganglion cocultures, we found that .times.-opiate receptors are negatively coupled to adenylate cyclase. The .times.-opiate agonists (e.g., U50488) inhibit significantly and dose-dependently the basal and the forskolin-stimulated cyclase activities, whereas .mu. and .delta. agonists are ineffective. The regulatory action is stereospecific and requires the presence of GTP. EGTA treatment of the plasma membrane abolished the effect of .times.-opiate agonists on the basal cyclase activity, and this inhibitory effect could not be restored by subsequent addition of CA2+. The EGTA treatment did not affect the .times. agonist inhibition of the forskolin-stimulated cyclase. The results also show that following chronic exposure of cultured cells to etorphine or U50488, there is a loss of .times. agonist inhibition of the cyclase. Moreover, this desensitization process appears to be heterologous, because .alpha.2-adrenergic agonists (e.g., clonidine or norepinephrine) and the muscarinic agonist (carbachol) exhibited significantly lower potency for inhibiting cyclase activity when compared to untreated cultures. This pattern of heterologous desensitization suggests that chronic exposure to .times. opiates leads to alteration in postreceptor regulatory components, possibly GTP-binding proteins.