The selective mu‐opioid receptor antagonist adl5510 reduces levodopa‐induced dyskinesia without affecting antiparkinsonian action in mptp‐lesioned macaque model of Parkinson's disease
Identifieur interne : 000115 ( Main/Exploration ); précédent : 000114; suivant : 000116The selective mu‐opioid receptor antagonist adl5510 reduces levodopa‐induced dyskinesia without affecting antiparkinsonian action in mptp‐lesioned macaque model of Parkinson's disease
Auteurs : James B. Koprich [Canada] ; Susan H. Fox [Canada] ; Tom H. Johnston [Canada] ; Allan Goodman [États-Unis] ; Bertrand Le Bourdonnec [États-Unis] ; Roland E. Dolle [États-Unis] ; Robert N. Dehaven [États-Unis] ; Diane L. Dehaven-Hudkins [États-Unis] ; Patrick J. Little [États-Unis] ; Jonathan M. Brotchie [Canada]Source :
- Movement Disorders [ 0885-3185 ] ; 2011-06.
English descriptors
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. © 2011 Movement Disorder Society
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DOI: 10.1002/mds.23631
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Disord.</title><idno type="ISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2011-06">2011-06</date><biblScope unit="volume">26</biblScope><biblScope unit="issue">7</biblScope><biblScope unit="page" from="1225">1225</biblScope><biblScope unit="page" to="1233">1233</biblScope></imprint><idno type="ISSN">0885-3185</idno></series><idno type="istex">94F7CFE250918B051E3754146840D304A9A1B30E</idno><idno type="DOI">10.1002/mds.23631</idno><idno type="ArticleID">MDS23631</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0885-3185</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>L‐DOPA</term><term>Parkinson's disease</term><term>dyskinesia</term><term>mu opioid antagonist</term><term>non‐human primate</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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. © 2011 Movement Disorder Society</div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>Pennsylvanie</li></region></list><tree><country name="Canada"><noRegion><name sortKey="Koprich, James B" sort="Koprich, James B" uniqKey="Koprich J" first="James B." last="Koprich">James B. Koprich</name></noRegion><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M." last="Brotchie">Jonathan M. Brotchie</name><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M." last="Brotchie">Jonathan M. Brotchie</name><name sortKey="Fox, Susan H" sort="Fox, Susan H" uniqKey="Fox S" first="Susan H." last="Fox">Susan H. Fox</name><name sortKey="Johnston, Tom H" sort="Johnston, Tom H" uniqKey="Johnston T" first="Tom H." last="Johnston">Tom H. Johnston</name><name sortKey="Johnston, Tom H" sort="Johnston, Tom H" uniqKey="Johnston T" first="Tom H." last="Johnston">Tom H. Johnston</name><name sortKey="Koprich, James B" sort="Koprich, James B" uniqKey="Koprich J" first="James B." last="Koprich">James B. Koprich</name></country><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Goodman, Allan" sort="Goodman, Allan" uniqKey="Goodman A" first="Allan" last="Goodman">Allan Goodman</name></region><name sortKey="Dehaven Udkins, Diane L" sort="Dehaven Udkins, Diane L" uniqKey="Dehaven Udkins D" first="Diane L." last="Dehaven-Hudkins">Diane L. Dehaven-Hudkins</name><name sortKey="Dehaven, Robert N" sort="Dehaven, Robert N" uniqKey="Dehaven R" first="Robert N." last="Dehaven">Robert N. Dehaven</name><name sortKey="Dolle, Roland E" sort="Dolle, Roland E" uniqKey="Dolle R" first="Roland E." last="Dolle">Roland E. Dolle</name><name sortKey="Le Bourdonnec, Bertrand" sort="Le Bourdonnec, Bertrand" uniqKey="Le Bourdonnec B" first="Bertrand" last="Le Bourdonnec">Bertrand Le Bourdonnec</name><name sortKey="Little, Patrick J" sort="Little, Patrick J" uniqKey="Little P" first="Patrick J." last="Little">Patrick J. Little</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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