POTENTIAL OF OPIOID ANTAGONISTS IN THE TREATMENT OF LEVODOPA-INDUCED DYSKINESIAS IN PARKINSONS-DISEASE

Current treatments for Parkinson's disease (PD) rely on dopamine-repla cing strategies, and centre around dopamine precursors (e.g. levodopa) or directly acting dopamine agonists. With long-term therapy these ag ents lose much of their clinical utility due to the appearance of adve rse effects such as dyskinesias and/or a wearing off of efficacy. Alth ough dyskinesias in Huntington's disease, hemiballism and experimental animals are thought to be associated with reductions in amino acid tr ansmission within the lateral and medial segments of the globus pallid us, 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, ac ting at delta and kappa opioid receptors, respectively, can reduce the release of amino acid transmitters. Furthermore, the synthesis of the se peptides appears to be enhanced in neurons projecting to the pallid al complex in animal models of PD following repeated treatment with do pamine-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 eff ects following long-term treatment, and do not elevate peptide synthes is when given de novo. These data, together with recent data on the be havioural 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 exte nd the time for which the antiparkinsonian effects of such compounds c an be usefully exploited.