Kato S, Fukuda K, Morikawa H, Shoda T, Mima H, Mori K
Department of Anesthesia, Kyoto University Hospital, Japan.
Eur J Pharmacol. 1998 Mar 19;345(2):221-8. doi: 10.1016/s0014-2999(98)00023-5.
To investigate cellular adaptation responses induced by chronic agonist treatment of the mu-opioid receptor, Chinese hamster ovary (CHO) cells were stably transfected with the rat mu-opioid receptor cDNA. Chronic treatment with agonists selective for the mu-opioid receptor, [D-Ala2, N-MePhe4, Gy-ol5]enkephalin (DAMGO), morphine and fentanyl, time- and dose-dependently induced down-regulation of the mu-opioid receptor. The down-regulation was not significantly affected by pretreatment with pertussis toxin, but was completely blocked by treatment with hypertonic sucrose, suggesting that receptor internalization mediated by clathrin-coated vesicles is an essential step in the mu-opioid receptor down-regulation. On the other hand, forskolin-stimulated cyclic AMP formation was increased by chronic DAMGO treatment, which was inhibited by pertussis toxin pretreatment. These results indicate that two adaptation responses induced by chronic agonist treatment of the mu-opioid receptor-expressing CHO cells, down-regulation of the mu-opioid receptor and supersensitization of adenylate cyclase, are mediated by distinct mechanisms.
为研究μ-阿片受体慢性激动剂处理诱导的细胞适应性反应，用大鼠μ-阿片受体cDNA稳定转染中国仓鼠卵巢（CHO）细胞。用对μ-阿片受体有选择性的激动剂[D-丙氨酸2，N-甲基苯丙氨酸4，甘氨酸-ol5]脑啡肽（DAMGO）、吗啡和芬太尼进行慢性处理，时间和剂量依赖性地诱导μ-阿片受体下调。下调不受百日咳毒素预处理的显著影响，但被高渗蔗糖处理完全阻断，提示网格蛋白包被小泡介导的受体内化是μ-阿片受体下调的关键步骤。另一方面，慢性DAMGO处理使福斯可林刺激的环磷酸腺苷形成增加，而百日咳毒素预处理可抑制此增加。这些结果表明，表达μ-阿片受体的CHO细胞经慢性激动剂处理诱导的两种适应性反应，即μ-阿片受体下调和腺苷酸环化酶超敏化，由不同机制介导。
