Alzheimer C, ten Bruggencate G
Department of Physiology, University of Munich, Federal Republic of Germany.
J Pharmacol Exp Ther. 1990 Nov;255(2):900-5.
The actions of the nonpeptide kappa-opioid receptor agonists, U 50488H (1-100 microM) and U 69593 (50-200 microM), on guinea pig hippocampal CA3 neurons were investigated in vitro by means of intra- and extracellular recording techniques. The compounds reduced the efficacy of synaptic transmission at the mossy fiber-CA3 synapse, and, simultaneously, enhanced the neuronal direct excitability. Intracellular recordings from CA3 neurons suggested two components underlying the drugs' excitatory actions: 1) Due to an apparent decrease in membrane leak conductance, the compounds enhanced the neuronal input resistance in a dose-dependent fashion. 2) The fast after-hyperpolarization following spontaneous or evoked action potentials was found to be substantially impaired in the presence of the drugs. In addition, extra- and intracellular recordings provided evidence that, by reducing the fast sodium conductance, both compounds exerted a local anesthetic action. The effects of U 50488H were antagonized neither by naloxone (2-50 microM) nor by the kappa-opioid receptor antagonist, nor-binaltorphimine (10-20 microM), indicating that the drug-induced effects represent unspecific actions not linked to activation of opioid receptors.
采用细胞内和细胞外记录技术，在体外研究了非肽类κ-阿片受体激动剂U 50488H（1 - 100微摩尔）和U 69593（50 - 200微摩尔）对豚鼠海马CA3神经元的作用。这些化合物降低了苔藓纤维-CA3突触处的突触传递效率，同时增强了神经元的直接兴奋性。对CA3神经元的细胞内记录表明，药物的兴奋作用有两个成分：1）由于膜漏电导明显降低，这些化合物以剂量依赖的方式增强了神经元的输入电阻。2）发现在药物存在的情况下，自发或诱发动作电位后的快速超极化后电位明显受损。此外，细胞外和细胞内记录提供了证据，即通过降低快速钠电导，这两种化合物都发挥了局部麻醉作用。U 50488H的作用既不被纳洛酮（2 - 50微摩尔）拮抗，也不被κ-阿片受体拮抗剂 nor - binaltorphimine（10 - 20微摩尔）拮抗，这表明药物诱导的效应代表与阿片受体激活无关的非特异性作用。
