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- Bezard, Erwan, et al.
(författare)
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mu Opioid Receptor Agonism for L-DOPA-Induced Dyskinesia in Parkinson's Disease
- 2020
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Ingår i: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 40:35, s. 6812-6819
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson's disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine precursor L-DOPA, but its prolonged usage causes dyskinesias referred to as L-DOPA-induced dyskinesia (LID). Several studies in animal models of PD have suggested that dyskinesias are associated with a heightened opioid cotransmitter tone, observations that have led to the notion of a LID-related hyperactive opioid transmission that should be corrected by mu opioid receptor antagonists. Reports that both antagonists and agonists of the mu opioid receptor may alleviate LID severity in primate models of PD and LID, together with the failure of nonspecific antagonist to improve LID in pilot clinical trials in patients, raises doubt about the reliability of the available data on the opioid system in PD and LID. After in vitro characterization of the functional activity at the mu opioid receptor, we selected prototypical agonists, antagonists, and partial agonists at the mu opioid receptor. We then showed that both oral and discrete intracerebral administration of a mu receptor agonist, but not of an antagonist as long thought, ameliorated LIDs in the gold-standard bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinelesioned female macaque model of PD and LID. The results call for a reappraisal of opioid pharmacology in the basal ganglia as well as for the development of brain nucleus-targeted mu opioid receptor agonists.
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- Iderberg, Hanna, et al.
(författare)
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Animal models of l-DOPA-induced dyskinesia: an update on the current options.
- 2012
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Ingår i: Neuroscience. - : Elsevier BV. - 1873-7544 .- 0306-4522. ; 211, s. 13-27
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Tidskriftsartikel (refereegranskat)abstract
- Major limitations to the pharmacotherapy of Parkinson's disease (PD) are the motor complications resulting from l-DOPA treatment. Abnormal involuntary movements (dyskinesia) affect a majority of the patients after a few years of l-DOPA treatment and can become troublesome and debilitating. Once dyskinesia has debuted, an irreversible process seems to have occurred, and the movement disorder becomes almost impossible to eliminate with adjustments in peroral pharmacotherapy. There is a great need to find new pharmacological interventions for PD that will alleviate parkinsonian symptoms without inducing dyskinesia. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned non-human primate model is an excellent symptomatic model of PD and was the first model used to reproduce l-DOPA-induced dyskinesia experimentally. As it recapitulates the motor features of human dyskinesia, that is, chorea and dystonia, it is considered a reliable animal model to define novel therapies. Over the last decade, rodent models of l-DOPA-induced dyskinesia have been developed, having both face validity and predictive validity. These models have now become the first-line experimental tool for therapeutic screening purposes. The application of classical 6-hydroxydopamine (6-OHDA) lesion procedures to produce rodent models of dyskinesia has provided the field with more dynamic tools, since the versatility of toxin doses and injection coordinates allows for mimicking different stages of PD. This article will review models developed in non-human primate and rodents to reproduce motor complications induced by dopamine replacement therapy. The recent breakthroughs represented by mouse models and the relevance of rodents in relation to non-human primate models will be discussed. This article is part of a Special Issue entitled: Neuroscience Disease Models.
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