Naloxone reduces levodopa-induced dyskinesias and apomorphine-induced rotations in primate models of parkinsonism.
Using in situ hybridization, it was found that subchronic treatment with levodopa/benserazide increased preproenkephalin-A and preproenkephalin-B mRNAs in the dopamine-depleted striatum. In order to examine whether dysfunction of the endogenous opioid system may underlie the development of levodopa-induced dyskinesias, the effect of naloxone, an opioid antagonist, on dyskinesias was investigated in two models of parkinsonism in the common marmoset. MPTP-treated monkeys were administered a daily oral dose of levodopa/benserazide which relieved the parkinsonian symptoms but induced severe and reproducible dyskinetic movements. Naloxone (0.1, 0.2 or 0.5 mg/kg) was given subcutaneously (s.c.) during peak-dose dyskinesia, which reduced the dyskinesias significantly using the highest dose, normalized the motor activity, but did not modify the antiparkinson effect. Unilaterally 6-OHDA -lesioned marmosets received apomorphine s.c., which caused a contralateral turning behavior that could be reduced up to 35 percent by concomitant administration of naloxone. Taken together the present results suggest a possible role for the endogenous opioid system in the pathogenesis of levodopa-induced dyskinesia in primates.
Klintenberg
R
R
Department of Pharmaceutical Biosciences, Uppsala University, Biomedicum, Uppsala, Sweden.
Svenningsson
P
P
Gunne
L
L
Andrén
P E
PE
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001545:Benserazide / Q000494:pharmacology; D002144:Callithrix; D004298:Dopamine / Q000502:physiology; D015259:Dopamine Agents / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000633:toxicity*; D004409:Dyskinesia, Drug-Induced / Q000517:prevention & control* / Q000523:psychology; D004745:Enkephalins / Q000096:biosynthesis; D005260:Female; D017403:In Situ Hybridization; D007980:Levodopa / Q000037:antagonists & inhibitors / Q000633:toxicity*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000503:physiopathology* / Q000523:psychology; D011498:Protein Precursors / Q000096:biosynthesis; D012313:RNA / Q000096:biosynthesis; D012399:Rotation; D013239:Stereotyped Behavior / Q000187:drug effects*; D013563:Sympathectomy, Chemical
D015259:Dopamine Agents; D018492:Dopamine Antagonists; D004745:Enkephalins; D009292:Narcotic Antagonists; D011498:Protein Precursors; D009270:Naloxone; D007980:Levodopa; D012313:RNA; D001545:Benserazide; D016627:Oxidopamine; C033660:preproenkephalin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine