Potential of Opioid Antagonists in the Treatment of Levodopa-Induced Dyskinesias in Parkinson??s Disease

Abstract

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.

Endomorphin-1: Induction of Motor Behavior and Lack of Receptor Desensitization

“…NALOX, Naloxone; ENDO, endomorphin-1; VEH, vehicle. apomorphine-induced rotations in rats with unilateral nigrostriatal lesions (Henry and Brotchie, 1996), whereas cyprodime, a selective -opioid receptor antagonist, had no effect on the behavior (Henry and Brotchie, 1996).…”

Do Preclinical Findings of Methamphetamine-Induced Motor Abnormalities Translate to an Observable Clinical Phenotype?

“…While these methods are useful for distinguishing the relevance of a particular dopamine subsystem (eg D1 or D2), these pharmacologic manipulations impose changes to neuronal systems that, even in the absence of MA coadministration, can alter motor behavior. In fact, opioid peptides have been employed for years as a potential adjunctive treatment for Parkinson's disease (Giuffra et al, 1993;Hille et al, 2001) and its complications (Henry and Brotchie, 1996). Nevertheless, this work has led to a greater understanding of the role of MA in behavioral disturbances regulated by the dopamine via the direct and indirect striatopallidal GABAergic pathways and their translation to movement disorders humans.…”

Persistent Behavioral Sensitization to Chronic l-DOPA Requires A2AAdenosine Receptors

“…Such shortcomings of L-DOPA and other dopaminergic drugs have prompted a search for alternative treatment strategies that provide symptomatic benefits while avoiding the delayed motor complications associated with the long-term use of antiparkinsonian drugs. Several neurotransmitters have been implicated in the motor complications elicited by repeated dopamine receptor stimulation, including glutamate (Marin et al, 1996;Tzschentke and Schmidt, 1998;Calabresi et al, 2000), cannabinoids (Souilhac et al, 1995;Zeng et al, 1999), opioids (Henry and Brotchie, 1996), and adenosine (Richardson et al, 1997;Kanda et al, 2000;Jenner, 2000). Recently, the A 2A adenosine receptor has emerged as an attractive target for PD treatment by virtue of its concentrated expression in striatopallidal neurons and its modulation of dopamine receptor-mediated functions (Schiffmann et al, 1991;Fink et al, 1992;Ferré et al, 1997;Svenningsson et al, 1999).…”