Samadi Pershia, Bédard Paul J, Rouillard Claude
Centre de Recherche en Endocrinologie Moléculaire et Oncologie, Centre Hospitalier Universitaire de Québec, and Faculté de Pharmacie, Université Laval, Québec, G1V 4G2, Canada.
Trends Pharmacol Sci. 2006 Oct;27(10):512-7. doi: 10.1016/j.tips.2006.08.002. Epub 2006 Sep 5.
The long-term treatment of Parkinson's disease with L-dopa is often associated with the appearance of involuntary movements called L-dopa-induced dyskinesias. These debilitating side-effects are thought to result from an aberrant form of plasticity triggered by a combination of factors related to dopamine denervation and repeated L-dopa administration. In animal models of Parkinson's disease, dopamine denervation and repeated L-dopa administration are associated with an enhancement of opioid transmission in the basal ganglia. The exact role of this increased opioid activity is still under debate. It has been proposed that some of the changes in opioid transmission are directly involved in the genesis of L-dopa-induced dyskinesias. In this article, we suggest that changes in opioid transmission in the basal ganglia in response to denervation and repeated L-dopa therapy are, instead, part of compensatory mechanisms to prevent motor complications. Initially, these compensatory mechanisms might be sufficient to attenuate the parkinsonian syndrome and delay the appearance of involuntary movements. But with the progression of the disease and repeated exposure to L-dopa, these mechanisms eventually fail. These new insights could contribute to better understanding of the motor complications in Parkinson's disease and lead to the development or improvement of pharmacological strategies to prevent or reduce L-dopa-induced dyskinesias.
长期使用左旋多巴治疗帕金森病常常会出现一种称为左旋多巴诱导性运动障碍的不自主运动。这些使人衰弱的副作用被认为是由与多巴胺去神经支配及反复给予左旋多巴相关的多种因素引发的异常可塑性形式所致。在帕金森病动物模型中，多巴胺去神经支配和反复给予左旋多巴与基底神经节中阿片类物质传递增强有关。这种阿片类物质活性增加的确切作用仍在争论中。有人提出，阿片类物质传递的一些变化直接参与了左旋多巴诱导性运动障碍的发生。在本文中，我们认为，基底神经节中阿片类物质传递因去神经支配和反复左旋多巴治疗而发生的变化，相反，是预防运动并发症的代偿机制的一部分。最初，这些代偿机制可能足以减轻帕金森综合征并延迟不自主运动的出现。但随着疾病进展和反复接触左旋多巴，这些机制最终会失效。这些新见解有助于更好地理解帕金森病的运动并发症，并促使开发或改进预防或减少左旋多巴诱导性运动障碍的药理学策略。
