Henry B, Brotchie J M
Division of Neuroscience, School of Biological Sciences, University of Manchester, England.
Drugs Aging. 1996 Sep;9(3):149-58. doi: 10.2165/00002512-199609030-00001.
Current treatments for Parkinson's disease (PD) rely on dopamine-replacing strategies, and centre around dopamine precursors (e.g. levodopa) or directly acting dopamine agonists. With long-term therapy these agents lose much of their clinical utility due to the appearance of adverse effects such as dyskinesias and/or a wearing off of efficacy. Although dyskinesias in Huntington's disease, hemiballism and experimental animals are thought to be associated with reductions in amino acid transmission within the lateral and medial segments of the globus pallidus, the neural mechanisms underlying treatment-related dyskinesias in PD are poorly understood. Recent evidence suggests that, within these regions of the brain, the opioid peptides enkephalin and dynorphin, acting at delta and kappa opioid receptors, respectively, can reduce the release of amino acid transmitters. Furthermore, the synthesis of these peptides appears to be enhanced in neurons projecting to the pallidal complex in animal models of PD following repeated treatment with dopamine-replacing agents that also cause dyskinetic adverse effects (e.g. levodopa and apomorphine). In contrast, dopamine receptor agonists such as bromocriptine and lisuride do not cause dyskinetic adverse effects following long-term treatment, and do not elevate peptide synthesis when given de novo. These data, together with recent data on the behavioural effects of opioid antagonists in a rodent model of levodopa-induced dyskinesia in PD, suggest the possibility that antagonists of opioid receptors may prove useful as adjuncts to levodopa. By limiting the severity of dyskinetic adverse effects, these drugs may help extend the time for which the antiparkinsonian effects of such compounds can be usefully exploited.
帕金森病（PD）的现有治疗方法依赖于多巴胺替代策略，主要围绕多巴胺前体（如左旋多巴）或直接作用的多巴胺激动剂。长期使用这些药物后，由于出现异动症和/或疗效减退等不良反应，它们的临床效用会大打折扣。虽然亨廷顿舞蹈病、偏身投掷症及实验动物中的异动症被认为与苍白球外侧和内侧节段内氨基酸传递减少有关，但PD中与治疗相关的异动症的神经机制却知之甚少。最近的证据表明，在大脑的这些区域，分别作用于δ和κ阿片受体的阿片肽脑啡肽和强啡肽可以减少氨基酸递质的释放。此外，在PD动物模型中，用同样会引起异动症不良反应的多巴胺替代药物（如左旋多巴和阿扑吗啡）反复治疗后，投射到苍白球复合体的神经元中这些肽的合成似乎会增强。相比之下，多巴胺受体激动剂如溴隐亭和利苏瑞得在长期治疗后不会引起异动症不良反应，初次给药时也不会提高肽的合成。这些数据，连同最近关于阿片受体拮抗剂在PD左旋多巴诱导的异动症啮齿动物模型中的行为效应的数据，表明阿片受体拮抗剂可能作为左旋多巴的辅助药物有用的可能性。通过限制异动症不良反应的严重程度，这些药物可能有助于延长此类化合物抗帕金森病作用可有效利用的时间。
