Sheng J Z, Wong T M
Department of Physiology, Faculty of Medicine, University of Hong Kong, Hong Kong.
Eur J Pharmacol. 1996 Jul 4;307(3):323-9. doi: 10.1016/0014-2999(96)00280-4.
The inositol 1,4,5-trisphosphate (IP3) content and intracellular free Ca2+ ([Ca2+]i) level in response to kappa-opioid receptor stimulation with selective kappa-opioid receptor agonists, dynorphin-(1-13) and trans-3,4-dichloro-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeacetamidel (U50,488H) were determined in ventricular myocytes. Both IP3 and [Ca2+]i were increased following kappa-opioid receptor stimulation. The responses of IP3 and [Ca2+]i to kappa-opioid receptor stimulation were abolished in myocytes of rats that had received chronic injection of U50,488H for 4 days. kappa-Opioid receptor stimulation with U50,488H also reduced the [Ca2+]i transient, induced by electrical stimulation and caffeine, both known to mobilize [Ca2+]i. The effect was abolished after the myocytes had been incubated with U50,488H at a subthreshold concentration for its effect on [Ca2+]i for 24 h. The present study showed for the first time that, upon the development of tolerance to a kappa-opioid receptor agonist, the responses of IP3 and [Ca2+]i to kappa-opioid receptor stimulation were abolished. The lack of response in [Ca2+]i was due to a failure of mobilization of Ca2+ from its intracellular pool. Further study is needed to determine the events that occur after the kappa-opioid receptor stimulation to production of IP3 upon the development of tolerance to a kappa-opioid.
在心室肌细胞中测定了用选择性κ-阿片受体激动剂强啡肽-(1 - 13)和反式-3,4 - 二氯 - N - [2 - (1 - 吡咯烷基)环己基]苯乙酰胺(U50,488H)刺激κ-阿片受体后肌醇1,4,5 - 三磷酸(IP3)含量和细胞内游离Ca2+( [Ca2+]i)水平。κ-阿片受体刺激后，IP3和[Ca2+]i均升高。在接受U50,488H慢性注射4天的大鼠的心肌细胞中，IP3和[Ca2+]i对κ-阿片受体刺激的反应消失。用U50,488H刺激κ-阿片受体也降低了由电刺激和咖啡因诱导的[Ca2+]i瞬变，已知这两者均可动员[Ca2+]i。在用低于阈值浓度的U50,488H孵育心肌细胞24小时后，其对[Ca2+]i的作用消失。本研究首次表明，在对κ-阿片受体激动剂产生耐受性后，IP3和[Ca2+]i对κ-阿片受体刺激的反应消失。[Ca2+]i缺乏反应是由于Ca2+从其细胞内储存库动员失败。需要进一步研究以确定在对κ-阿片受体产生耐受性后，κ-阿片受体刺激后产生IP3的过程中发生的事件。
