Opioid antagonists increase the dyskinetic response to dopaminergic agents in parkinsonian monkeys: interaction between dopamine and opioid systems.
The pathogenesis of levodopa-induced dyskinesias (LID) still remains obscure. It has been suggested that enhanced opioidergic transmission in striatal output pathways may play a role in the induction of LID. To test this hypothesis, we have investigated the effect of different doses of the opioid receptor antagonists, naloxone and naltrexone on the dyskinetic response to a D1 agonist SKF 82958, a D2 agonist quinpirole and L-3,4-dihydroxyphenylalanine (L-Dopa). We have used six female cynomolgus monkeys rendered parkinsonian by the toxin MPTP and presenting a stable parkinsonian syndrome. All responded to L-Dopa and had developed dyskinesias which were manifested with each dose. The parkinsonian syndrome and dyskinesias were evaluated for each animal and scored after the treatments. Locomotor activity was measured by an electronic motility monitoring system. Our results show that coadministration of naloxone or naltrexone with dopaminergic agents leads to a significant increase in the severity of dyskinesias without noticeable effect on the antiparkinsonian efficacy of the treatment. These results suggest that increased opioidergic transmission in the two major striatal output pathways in monkeys or humans with LID might be an attempt to dampen the effect of abnormal dopaminergic stimulation rather than the cause of dyskinesias.
Unité de recherche en Neuroscience, Le Centre Hospitalier Universitaire de Québec, Pavillon CHUL, 2705 Boulevard Laurier, Sainte-Foy, Quebec G1V 4G2, Canada.
Pershia
P
Samadi
Laurent
L
Grégoire
Paul J
PJ
Bédard
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D015259:Dopamine Agents / Q000633:toxicity*; D018491:Dopamine Agonists / Q000494:pharmacology; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology*; D004723:Endorphins / Q000502:physiology*; D005260:Female; D007980:Levodopa / Q000494:pharmacology; D008252:Macaca fascicularis; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000503:physiopathology*; D019257:Quinpirole / Q000494:pharmacology; D017447:Receptors, Dopamine D1 / Q000819:agonists; D017448:Receptors, Dopamine D2 / Q000819:agonists; D009435:Synaptic Transmission / Q000187:drug effects
D001552:Benzazepines; D015259:Dopamine Agents; D018491:Dopamine Agonists; D004723:Endorphins; D009292:Narcotic Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D009270:Naloxone; D007980:Levodopa; D009271:Naltrexone; C071262:SK&F 82958; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine