Ochoa M C, Vogelsang G D, Lum J T, VonVoigtlander P F, Piercey M F
CNS Research, Upjohn Company, Kalamazoo, MI 49001.
Life Sci. 1992;50(17):1225-33. doi: 10.1016/0024-3205(92)90322-g.
U-54494A, a 1,2-diamine anticonvulsant, and U-50488H, a structurally related agonist for opiate kappa receptors, were tested for effects on spontaneous and glutamate-evoked firing rates in cerebral cortex of urethane-anesthetized male Sprague-Dawley rats. Iontophoretic application of 1,2-diamines, glutamate diethyl ether (GDEE), or procaine depressed spontaneous and amino acid-induced firing of cortical neurones. With continued ejection of 1,2-diamines or procaine, firing was silenced completely, but GDEE could maintain a partial suppression. A rapid rebound of excitation followed cessation of procaine ejections, but not of other agents. Procaine, but not U-54494A, blocked axonal conduction of rabbit sciatic nerve. Intravenous U-54494A and U-50488H significantly depressed spontaneous firing rates of cortical neurones, but only the U-50488H effects were antagonized by naloxone. It is concluded that U-54494A inhibits neuronal excitability by a mechanism independent of the analgesic kappa receptor. Biochemical and physiological studies have demonstrated that U-54494A and the kappa opioid agonist U-50488H (a structurally related diamine) (1) have anticonvulsant activity (2, 3). U-54494A lacks kappa analgesic and sedative properties, and it has been suggested that the mechanism of action of this compound may be mediated by a subtype of kappa opioid receptor (3). The effects of kappa analgesics on neuronal firing in nociceptive pathways have been described (4, 5). However, no previous electrophysiological studies on U-54494A have been done. Since U-54494A antagonizes amino acid-induced seizures (3), the interactions of this compound with glutamate are of interest. In the present study, the antagonist efficacies of U-54494A and U-50488H for inhibiting spontaneous and 1-glutamate stimulated neurons of the rat prefrontal cerebral cortex were assessed after i.v. and microiontophoretic administration of the compounds. Effects observed with these routes of administration allow the observation of neuronal changes occurring immediately after administration and take advantage of the high temporal resolution provided by the electrophysiological recording techniques of single cells. A preliminary account of portions of this work have been previously disclosed (6).
对1,2 -二胺类抗惊厥药U - 54494A以及结构相关的阿片κ受体激动剂U - 50488H，在乌拉坦麻醉的雄性斯普拉格 - 道利大鼠大脑皮层中，测试它们对自发放电率和谷氨酸诱发放电率的影响。离子电渗法施加1,2 -二胺、谷氨酸二乙醚（GDEE）或普鲁卡因可抑制皮层神经元的自发放电以及氨基酸诱发的放电。持续喷射1,2 -二胺或普鲁卡因会使放电完全停止，但GDEE可维持部分抑制作用。停止喷射普鲁卡因后会迅速出现兴奋反弹，但其他药物不会。普鲁卡因可阻断兔坐骨神经的轴突传导，而U - 54494A则不能。静脉注射U - 54494A和U - 50488H可显著降低皮层神经元的自发放电率，但只有U - 50488H的作用可被纳洛酮拮抗。得出的结论是，U - 54494A通过一种独立于镇痛κ受体的机制抑制神经元兴奋性。生化和生理学研究表明，U - 54494A和κ阿片激动剂U - 50488H（一种结构相关的二胺）（1）具有抗惊厥活性（2,3）。U - 54494A缺乏κ镇痛和镇静特性，有人提出该化合物的作用机制可能由κ阿片受体的一个亚型介导（3）。已经描述了κ镇痛药对伤害性感受通路中神经元放电的影响（4,5）。然而，此前尚未对U - 54494A进行过电生理学研究。由于U - 54494A可拮抗氨基酸诱发的癫痫发作（3），因此该化合物与谷氨酸的相互作用值得关注。在本研究中，静脉注射和微量离子电渗法给予化合物后，评估了U - 54494A和U - 50488H对大鼠前额叶大脑皮层中抑制自发和L -谷氨酸刺激神经元的拮抗效力。通过这些给药途径观察到的效应，能够观察给药后立即发生的神经元变化，并利用单细胞电生理记录技术提供的高时间分辨率。这项工作部分内容的初步报告先前已经披露（6）。
