Antiparkinsonian action of a delta opioid agonist in rodent and primate models of Parkinson's disease.
The opioid peptides localized in striatal projection neurons are of great relevance to Parkinson's disease, not only as a consequence of their distribution, but also due to the pronounced changes in expression seen in Parkinson's disease. It has long been suspected that increased expression of enkephalin may represent one of the many mechanisms that compensate for dopamine (DA) depletion in Parkinson's disease. Here we demonstrate that a systemically delivered, selective delta opioid agonist (SNC80) has potent antiparkinsonian actions in both rat and primate models of Parkinson's disease. In rats treated with either the D2-preferring DA antagonist haloperidol (1 mg/kg) or the selective D1 antagonist SCH23390 (1 mg/kg), but not a combination of D1 and D2 antagonists, SNC80 (10 mg/kg) completely reversed the catalepsy induced by DA antagonists. In rats rendered immobile by treatment with reserpine, SNC80 dose-dependently reversed akinesia (EC(50) 7.49 mg/kg). These effects were dose-dependently inhibited (IC(50) 1.05 mg/kg) by a selective delta opioid antagonist (naltrindole) and by SCH23390 (1 mg/kg), but not by haloperidol (1 mg/kg). SNC80 also reversed parkinsonian symptoms in the MPTP-treated marmoset. At 10 mg/kg (ip), scores measuring bradykinesia and posture were significantly reduced and motor activity increased to levels comparable with pre-MPTP-treatment scores. Any treatment that serves to increase delta opioid receptor activation may be a useful therapeutic strategy for the treatment of Parkinson's disease, either in the early stages or as an adjunct to dopamine replacement therapy. Furthermore, enhanced enkephalin expression observed in Parkinson's disease may serve to potentiate dopamine acting preferentially at D1 receptors.
Hille
C J
CJ
Department of Pharmacology, University of Oxford, Oxford OX1 3QT, United Kingdom.
Fox
S H
SH
Maneuf
Y P
YP
Crossman
A R
AR
Brotchie
J M
JM
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000627:therapeutic use*; D002144:Callithrix; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009292:Narcotic Antagonists / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy*; D010879:Piperazines / Q000627:therapeutic use*; D011187:Posture; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000037:antagonists & inhibitors; D012110:Reserpine / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D001549:Benzamides; D018492:Dopamine Antagonists; D009292:Narcotic Antagonists; D010879:Piperazines; D017465:Receptors, Opioid, delta; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D012110:Reserpine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine