title: The selective mu-opioid receptor antagonist ADL5510 reduces levodopa-induced dyskinesia without affecting antiparkinsonian action in MPTP-lesioned macaque model of Parkinson's disease.
abstract: In Parkinson's disease (PD), dyskinesia develops following long-term treatment with 3,4-dihydroxyphenylalanine (L-dopa). Given the prominent role of the opioid system in basal ganglia function, nonselective opioid receptor antagonists have been tested for antidyskinetic efficacy in the clinic (naltrexone and naloxone), although without success. In the current study, ADL5510, a novel, orally active opioid antagonist with mu opioid receptor selectivity, was examined in L-dopa-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaques. Antidyskinetic effects were compared with those of naltrexone. Parkinsonian monkeys with established L-dopa-induced dyskinesia (LID) received acute challenges with L-dopa (subcutaneously) in combination with either vehicle, ADL5510 (0.1, 1, 3 or 10 mg/kg by mouth), or naltrexone (1, 3, or 10 mg/kg subcutaneously). Following treatments, behavior was monitored for 6 hours. Parameters assessed were total activity, parkinsonism, and dyskinesia. ADL5510 (1, 3, and 10 mg/kg) reduced activity and LID (chorea and dystonia) without affecting the antiparkinsonian benefits of L-dopa. The antidyskinetic effect of ADL5510 showed a U-shaped dose-response. It was inactive at 0.1 mg/kg, efficacious at 1 and 3 mg/kg (72% and 40% reductions, respectively), and then less effective at 10 mg/kg. The quality of ON time produced by L-dopa was improved, as indicated by a reduction in the percentage of ON time spent experiencing disabling dyskinesia (70% and 61% reductions with 1 and 3 mg/kg, respectively, compared with L-dopa). Naltrexone, in contrast, did not alleviate LID or affect the antiparkinsonian actions of L-dopa. Mu-selective opioid antagonists have the potential to form the basis of novel antidyskinetic therapies for PD.
authors.affiliation: Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
authors.forename: James B
authors.initials: JB
authors.lastname: Koprich
authors.forename: Susan H
authors.initials: SH
authors.lastname: Fox
authors.forename: Tom H
authors.initials: TH
authors.lastname: Johnston
authors.forename: Allan
authors.initials: A
authors.lastname: Goodman
authors.forename: Bertrand
authors.initials: B
authors.lastname: Le Bourdonnec
authors.forename: Roland E
authors.initials: RE
authors.lastname: Dolle
authors.forename: Robert N
authors.initials: RN
authors.lastname: DeHaven
authors.forename: Diane L
authors.initials: DL
authors.lastname: DeHaven-Hudkins
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Little
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Brotchie
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007980:Levodopa / Q000633:toxicity*; D008252:Macaca fascicularis; D008297:Male; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*
chemical_list: D000978:Antiparkinson Agents; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D007980:Levodopa; D009271:Naltrexone