Choi D W, Viseskul V
Department of Neurology, Stanford University Medical Center, CA 94305.
Eur J Pharmacol. 1988 Oct 11;155(1-2):27-35. doi: 10.1016/0014-2999(88)90399-8.
Addition of 1 microM-1 mM methadone to the bathing medium produced a concentration-dependent reduction in the neurotoxicity of exogenously applied N-methyl-D-aspartate (NMDA) in murine cortical cell culture (EC50 about 100 microM); the reduction persisted at intense NMDA exposure, consistent with non-competitive inhibition. Methadone also protected against exposure to quinolinate but not quisqualate or kainate. Concentrations (100 microM-3 mM) of several other opioids - morphine, fentanyl, codeine, meperidine, dextropropoxyphene, and naltrexone - were additionally found to produce concentration-dependent reductions in NMDA neurotoxicity. This novel neuron-protective effect of opioids was not mediated by conventional opioid receptors: the non-opioid enantiomer of methadone and morphine exhibited a potency equal to or greater than that of the opioid enantiomer, and 1 mM naloxone did not act as an antagonist. The possibility that opioids, or especially non-opioid enantiomers of opioids, might provide a useful therapeutic approach in diseases states involving NMDA receptor-mediated neurotoxicity, warrants further study.
在小鼠皮层细胞培养中，向浴液中添加1微摩尔至1毫摩尔的美沙酮可使外源性应用的N-甲基-D-天冬氨酸（NMDA）的神经毒性呈浓度依赖性降低（半数有效浓度约为100微摩尔）；在强烈NMDA暴露下这种降低仍然存在，这与非竞争性抑制一致。美沙酮还可保护细胞免受喹啉酸暴露的影响，但对quisqualate或海人藻酸无保护作用。此外还发现，几种其他阿片类药物——吗啡、芬太尼、可待因、哌替啶、右丙氧芬和纳曲酮——的浓度（100微摩尔至3毫摩尔）也可使NMDA神经毒性呈浓度依赖性降低。阿片类药物这种新的神经保护作用并非由传统阿片受体介导：美沙酮和吗啡的非阿片对映体表现出的效力等于或大于阿片对映体，且1毫摩尔纳洛酮不起拮抗剂作用。阿片类药物，尤其是阿片类药物的非阿片对映体，可能在涉及NMDA受体介导的神经毒性的疾病状态中提供一种有用的治疗方法，这一可能性值得进一步研究。
