title: Dual κ-agonist/μ-antagonist opioid receptor modulation reduces levodopa-induced dyskinesia and corrects dysregulated striatal changes in the nonhuman primate model of Parkinson disease.
abstract: OBJECTIVE
  Effective medical management of levodopa-induced 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.
  
  
  METHODS
  1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated 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.
  
  
  RESULTS
  Nalbuphine reduced LID in a dose-dependent manner by 48% (p < 0.001) without compromising the anti-PD effect of levodopa or changing plasma levodopa levels. There was no tolerance to the anti-LID 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 ΔFosB, prodynorphin, dynorphin A, cyclin-dependent kinase 5, and increased phosphorylation of DARPP-32 at threonine-34.
  
  
  CONCLUSIONS
  Nalbuphine reverses the molecular milieu in the striatum associated with LID and is a safe and effective anti-LID agent in the primate model of PD. These findings support repurposing this analgesic for the treatment of LID.
authors.affiliation: Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Emory University, Atlanta, GA.
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Potts
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers Biomedical and Health Sciences-Robert Wood Johnson Medical School, Piscataway, NJ.
authors.forename: Eun S
authors.initials: ES
authors.lastname: Park
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers Biomedical and Health Sciences-Robert Wood Johnson Medical School, Piscataway, NJ.
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Woo
authors.affiliation: Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Emory University, Atlanta, GA.
authors.forename: Bhagya L
authors.initials: BL
authors.lastname: Dyavar Shetty
authors.affiliation: Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Emory University, Atlanta, GA.
authors.forename: Arun
authors.initials: A
authors.lastname: Singh
authors.affiliation: MentiNova, New Brunswick, NJ.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Braithwaite
authors.affiliation: MentiNova, New Brunswick, NJ.
authors.forename: Michael
authors.initials: M
authors.lastname: Voronkov
authors.affiliation: Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Emory University, Atlanta, GA.|Department of Neurology, Emory University School of Medicine, Atlanta, GA.
authors.forename: Stella M
authors.initials: SM
authors.lastname: Papa
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers Biomedical and Health Sciences-Robert Wood Johnson Medical School, Piscataway, NJ.|MentiNova, New Brunswick, NJ.
authors.forename: M Maral
authors.initials: MM
authors.lastname: Mouradian
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D005260:Female; D007980:Levodopa / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology; D008251:Macaca; D008297:Male; D009266:Nalbuphine / Q000008:administration & dosage / Q000494:pharmacology*; D017072:Neostriatum / Q000187:drug effects*; D010300:Parkinson Disease / Q000188:drug therapy*; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*
chemical_list: D000701:Analgesics, Opioid; D000978:Antiparkinson Agents; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D007980:Levodopa; D009266:Nalbuphine
references.citation: Neurology. 1998 May;50(5):1323-6
references.pmid: 9595981
references.citation: Clin Neuropharmacol. 2000 Mar-Apr;23(2):82-5
references.pmid: 10803797
references.citation: Neuropharmacology. 2003 Dec;45(7):954-63
references.pmid: 14573388
references.citation: J Neurosci Res. 2009 May 15;87(7):1645-58
references.pmid: 19115412
references.citation: Nature. 1999 Dec 9;402(6762):669-71
references.pmid: 10604473
references.citation: Exp Neurol. 2001 Sep;171(1):139-46
references.pmid: 11520128
references.citation: J Neurosci. 2007 Jun 27;27(26):6995-7005
references.pmid: 17596448
references.citation: Biol Psychiatry. 2007 Oct 1;62(7):800-10
references.pmid: 17662258
references.citation: J Neurosci. 2000 Dec 15;20(24):8965-71
references.pmid: 11124971
references.citation: Neuroscience. 1995 May;66(2):361-76
references.pmid: 7477878
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2191-6
references.pmid: 14769920
references.citation: J Pharm Biomed Anal. 1991;9(2):167-76
references.pmid: 1873308
references.citation: Neurobiol Dis. 2004 Jun;16(1):246-53
references.pmid: 15207281
references.citation: J Parkinsons Dis. 2012;2(3):189-98
references.pmid: 23938226
references.citation: Neuropharmacology. 2010 Jan;58(1):286-96
references.pmid: 19576910
references.citation: J Pharmacol Exp Ther. 2007 Oct;323(1):318-26
references.pmid: 17630359
references.citation: J Neural Transm (Vienna). 2002 Oct;109(10):1295-307
references.pmid: 12373562
references.citation: Neurobiol Dis. 2014 Feb;62:307-12
references.pmid: 24148855
references.citation: Ann Neurol. 2005 Jan;57(1):17-26
references.pmid: 15514976
references.citation: J Neurochem. 2008 Nov;107(4):1014-26
references.pmid: 18823371
references.citation: Neurobiol Dis. 1999 Dec;6(6):461-74
references.pmid: 10600402
references.citation: Ann Neurol. 1989 May;25(5):523-6
references.pmid: 2774496
references.citation: Eur J Pharmacol. 2009 Oct 12;620(1-3):42-8
references.pmid: 19686730
references.citation: Nat Neurosci. 2008 Aug;11(8):932-9
references.pmid: 18622401
references.citation: Neuron. 1999 Jul;23(3):435-47
references.pmid: 10433257
references.citation: Pharmacol Rev. 2013 Jan 10;65(1):171-222
references.pmid: 23319549
references.citation: J Neural Transm (Vienna). 1999;106(7-8):725-8
references.pmid: 10907730
references.citation: Ann Neurol. 1997 Nov;42(5):720-6
references.pmid: 9392571
references.citation: J Parkinsons Dis. 2011;1(4):347-57
references.pmid: 23933656
references.citation: Brain Res. 1991 Jun 21;552(1):113-8
references.pmid: 1717109
references.citation: Neurobiol Dis. 2001 Apr;8(2):220-39
references.pmid: 11300719
references.citation: J Comp Neurol. 1994 Dec 15;350(3):412-38
references.pmid: 7884049
references.citation: Neuroscience. 1995 Oct;68(4):1189-98
references.pmid: 8544992
references.citation: Biol Psychiatry. 2007 Apr 1;61(7):836-44
references.pmid: 16950226
references.citation: J Neuropathol Exp Neurol. 2002 Feb;61(2):186-96
references.pmid: 11853020
references.citation: Mov Disord. 2011 Jun;26(7):1225-33
references.pmid: 21465551
references.citation: Exp Neurol. 2007 May;205(1):101-7
references.pmid: 17335811
references.citation: J Pharmacol Exp Ther. 1988 Jan;244(1):391-402
references.pmid: 2826773
references.citation: PLoS One. 2010 Aug 23;5(8):e12322
references.pmid: 20808799
references.citation: Nat Rev Neurosci. 2008 Sep;9(9):665-77
references.pmid: 18714325
references.citation: Front Behav Neurosci. 2011 Oct 24;5:71
references.pmid: 22028687
references.citation: J Neurosci. 2010 May 26;30(21):7335-43
references.pmid: 20505100
references.citation: PLoS One. 2010 Dec 31;5(12):e15298
references.pmid: 21217832
references.citation: Neurobiol Dis. 2012 Jan;45(1):645-55
references.pmid: 22037042
references.citation: Mov Disord. 2004 May;19(5):554-60
references.pmid: 15133820
references.citation: Biol Psychiatry. 2001 Nov 15;50(10):813-6
references.pmid: 11720701
references.citation: Exp Neurol. 2003 Sep;183(1):66-73
references.pmid: 12957489
references.citation: Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21824-9
references.pmid: 21115823
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14845-50
references.pmid: 20682746
references.citation: Mov Disord. 1994 Jul;9(4):437-40
references.pmid: 7969211
references.citation: Neurobiol Dis. 2007 Mar;25(3):594-608
references.pmid: 17188499
references.citation: Science. 1990 Dec 7;250(4986):1429-32
references.pmid: 2147780
references.citation: Exp Neurol. 2003 Oct;183(2):458-68
references.pmid: 14552886
references.citation: Ann Neurol. 1996 May;39(5):574-8
references.pmid: 8619541
references.citation: Mov Disord. 2005 Aug;20(8):919-31
references.pmid: 16007614
references.citation: Nat Neurosci. 2003 May;6(5):501-6
references.pmid: 12665799
references.citation: Mol Cell Proteomics. 2011 Oct;10(10):M111.009308
references.pmid: 21737418
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2004 Apr 5;802(2):299-305
references.pmid: 15018791