{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T23:03:15Z","timestamp":1774047795373,"version":"3.50.1"},"reference-count":59,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2015,3,27]],"date-time":"2015-03-27T00:00:00Z","timestamp":1427414400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS073994"],"award-info":[{"award-number":["NS073994"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AT006868"],"award-info":[{"award-number":["AT006868"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2015,6]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Effective medical management of levodopa\u2010induced dyskinesia (LID) remains an unmet need for patients with Parkinson disease (PD). Changes in opioid transmission in the basal ganglia associated with LID suggest a therapeutic opportunity. Here we determined the impact of modulating both mu and kappa opioid receptor signaling using the mixed agonist\/antagonist analgesic nalbuphine in reducing LID and its molecular markers in the nonhuman primate model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>1\u2010Methyl\u20104\u2010phenyl\u20101,2,3,6\u2010tetrahydropyridine\u2013treated macaques with advanced parkinsonism and reproducible LID received a range of nalbuphine doses or saline subcutaneously as: (1) monotherapy, (2) acute coadministration with levodopa, and (3) chronic coadministration for 1 month. Animals were assessed by blinded examiners for motor disability and LID severity using standardized rating scales. Plasma levodopa levels were determined with and without nalbuphine, and postmortem brain samples were subjected to Western blot analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Nalbuphine reduced LID in a dose\u2010dependent manner by 48% (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) without compromising the anti\u2010PD effect of levodopa or changing plasma levodopa levels. There was no tolerance to the anti\u2010LID effect of nalbuphine given chronically. Nalbuphine coadministered with levodopa was well tolerated and did not cause sedation. Nalbuphine monotherapy had no effect on motor disability. Striatal tissue analyses showed that nalbuphine cotherapy blocks several molecular correlates of LID, including overexpression of \u0394FosB, prodynorphin, dynorphin A, cyclin\u2010dependent kinase 5, and increased phosphorylation of DARPP\u201032 at threonine\u201034.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Nalbuphine reverses the molecular milieu in the striatum associated with LID and is a safe and effective anti\u2010LID agent in the primate model of PD. These findings support repurposing this analgesic for the treatment of LID. Ann Neurol 2015;77:930\u2013941<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.24375","type":"journal-article","created":{"date-parts":[[2015,3,27]],"date-time":"2015-03-27T22:16:36Z","timestamp":1427494596000},"page":"930-941","source":"Crossref","is-referenced-by-count":44,"title":["Dual \u03ba\u2010agonist\/\u03bc\u2010antagonist opioid receptor modulation reduces levodopa\u2010induced dyskinesia and corrects dysregulated striatal changes in the nonhuman primate model of<scp>P<\/scp>arkinson disease"],"prefix":"10.1002","volume":"77","author":[{"given":"Lisa F.","family":"Potts","sequence":"first","affiliation":[{"name":"Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Emory University Atlanta GA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eun S.","family":"Park","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative and Neuroimmunologic Diseases Department of Neurology Rutgers Biomedical and Health Sciences\u2013Robert Wood Johnson Medical School Piscataway NJ"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jong\u2010Min","family":"Woo","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative and Neuroimmunologic Diseases Department of Neurology Rutgers Biomedical and Health Sciences\u2013Robert Wood Johnson Medical School Piscataway NJ"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bhagya L.","family":"Dyavar Shetty","sequence":"additional","affiliation":[{"name":"Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Emory University Atlanta GA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arun","family":"Singh","sequence":"additional","affiliation":[{"name":"Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Emory University Atlanta GA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven P.","family":"Braithwaite","sequence":"additional","affiliation":[{"name":"MentiNova New Brunswick NJ"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Voronkov","sequence":"additional","affiliation":[{"name":"MentiNova New Brunswick NJ"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stella M.","family":"Papa","sequence":"additional","affiliation":[{"name":"Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Emory University Atlanta GA"},{"name":"Department of Neurology Emory University School of Medicine Atlanta GA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Maral","family":"Mouradian","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative and Neuroimmunologic Diseases Department of Neurology Rutgers Biomedical and Health Sciences\u2013Robert Wood Johnson Medical School Piscataway NJ"},{"name":"MentiNova New Brunswick NJ"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,3,27]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.3233\/JPD-2012-120103"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.50.5.1323"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/00002826-200003000-00004"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0015298"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.20612"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2471"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M111.009308"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.111.005678"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(95)00120-8"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(94)00606-6"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/61.2.186"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-4886(03)00064-5"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.21978"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2009.06.030"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2013.10.016"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410420508"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2006.06.038"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1006\/nbdi.2000.0372"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.903500307"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0028-3908(03)00249-1"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.10693"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-002-0715-6"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.870090410"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1006\/exnr.2001.7727"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.23631"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-4886(03)00107-9"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2007.01.024"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2009.08.013"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s007020050192"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2004.02.002"},{"key":"e_1_2_8_32_1","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/S0022-3565(25)24238-0","article-title":"Nalbuphine: an autoradiographic opioid receptor binding profile in the central nervous system of an agonist\/antagonist analgesic","volume":"244","author":"De Souza EB","year":"1988","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.107.125666"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410390505"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2013.02.004"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/0731-7085(91)80140-5"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2003.12.006"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1006\/nbdi.1999.0259"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0252-10.2010"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(91)90667-K"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80798-9"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20296"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2006.11.001"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0012322"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3223(01)01234-3"},{"key":"e_1_2_8_46_1","doi-asserted-by":"crossref","unstructured":"FasanoS BezardE D'AntoniA et al.Inhibition of Ras\u2010guanine nucleotide\u2010releasing factor 1 (Ras\u2010GRF1) signaling in the striatum reverts motor symptoms associated with L\u2010dopa\u2010induced dyskinesia.Proc Natl Acad Sci U S A2010;107:21824\u201321829.","DOI":"10.1073\/pnas.1012071107"},{"key":"e_1_2_8_47_1","doi-asserted-by":"crossref","first-page":"347","DOI":"10.3233\/JPD-2011-11068","article-title":"Putaminal upregulation of FosB\/DeltaFosB\u2010like immunoreactivity in Parkinson's disease patients with dyskinesia","volume":"1","author":"Lindgren HS","year":"2011","journal-title":"J Parkinsons Dis"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1040"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2011.00071"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2006.113050"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0852-07.2007"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1009874107"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410250521"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2153"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2008.05702.x"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2011.10.011"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/45251"},{"key":"e_1_2_8_58_1","doi-asserted-by":"crossref","unstructured":"CherguiK SvenningssonP GreengardP.Cyclin\u2010dependent kinase 5 regulates dopaminergic and glutamatergic transmission in the striatum.Proc Natl Acad Sci U S A2004;101:2191\u20132196.","DOI":"10.1073\/pnas.0308652100"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-24-08965.2000"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2006.11.032"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fana.24375","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.24375","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T18:01:52Z","timestamp":1747850512000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.24375"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,3,27]]},"references-count":59,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2015,6]]}},"alternative-id":["10.1002\/ana.24375"],"URL":"https:\/\/doi.org\/10.1002\/ana.24375","archive":["Portico"],"relation":{},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,3,27]]}}}