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 r elevance to Parkinson's disease, not only as a consequence of their distrib ution, but also due to the pronounced changes in expression seen in Parkins on's disease. It has long been suspected that increased expression of enkep halin may represent one of the many mechanisms that compensate for dopamine (DA) depletion in Parkinson's disease. Here we demonstrate that a systemic ally delivered, selective 8 opioid agonist (SNC80) has potent antiparkinson ian 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) o r 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 i nduced by DA antagonists. In rats rendered immobile by treatment with reser pine, SNC80 dose-dependently reversed akinesia (EC50 7.49 mg/kg). These eff ects were dose-dependently inhibited (IC50 1.05 mg/kg) by a selective delta opioid antagonist (naltrindole) and by SCH23390 (1 mg/kg), but not by halo peridol (1 mg/kg). SNC80 also reversed parkinsonian symptoms in the MPTP-tr eated marmoset. At 10 mg/kg (ip), scores measuring bradykinesia and posture were significantly reduced and motor activity increased to levels comparab le with pre-MPTP-treatment scores. Any treatment that serves to increase de lta opioid receptor activation may be a useful therapeutic strategy for the treatment of Parkinson's disease, either in the early stages or as an adju nct to dopamine replacement therapy. Furthermore, enhanced enkephalin expre ssion observed in Parkinson's disease may serve to potentiate dopamine acti ng preferentially at D1 receptors. (C) 2001 Academic Press.