Several lines of evidence demonstrate that the striatal enkephalinergic system may be involved in the development of LIDs. Preproenkephalin-B (PPE-B) transcript levels are elevated with LIDs and there are also declines in kappa-opioid and other opioid receptors in different regions of the basal ganglia. If reduced kappa-opioid receptors are linked to LIDs, it is possible that drugs that stimulate this subtype may decrease dyskinesias. We therefore initiated experiments to investigate the effect of kappa-opioid receptor activation on LIDs. We first tested the selective kappa-agonist U50,488 in rats with unilateral lesions of the nigrostriatal pathway. Chronic L-dopa treatment induced abnormal involuntary movements, including axial, orolingual and forelimb dyskinesias contralateral to the lesion. U50,488 administration prior to L-dopa treatment reduced these movements by 70%, suggesting that U50,488 has potential as an anti-dyskinetic treatment. We next tested its effect in a parkinsonian nonhuman primate model, which offers the advantage that parkinsonism and LIDs can clearly be differentiated and that the dyskinesias are similar to those in parkinsonian patients. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys were treated with L-dopa (5 mg/kg p.o.) twice daily for 3 weeks to induce dyskinesias. As in the rodent model, U50,488 (0.1-1.0 mg/kg i.m.) decreased LIDs in a dose-dependent fashion. However, the anti-parkinsonian effect of L-dopa was similarly reduced, and side effects developed, including sedation and vomiting. These data suggest that kappa-opioid agonists such as U50,488 may not be clinically useful antidyskinetic agents because they also reverse the anti-parkinsonian effect of l-dopa.