Effects of U-50488H on dyskinesia induced by repeated dosing with L-DOPA in MPTP-treated cynomolgus monkeys

It is well known that L-DOPA improves Parkinsonian symptoms. However, with chronic treatment with L-DOPA, dyskinesia develops in most patients. The pathogenic mechanism of dyskinesia is not fully understood. A mu-opioid receptor antagonist, naloxone, has been reported to suppress dyskinesia in monkeys. Kappa-opioid receptor agonists produce several pharmacological effects opposite to those produced by mu-opioid receptor agonists, suggesting that activation of kappa-opioid receptors may suppress the dyskinesia. In this study, effects of U-50488H, a kappa-opioid receptor agonist, on L-DOPA-induced dyskinesia were evaluated in MPTP-treated cynomolgus monkeys. As a result, U-50488H reduced dyskinetic movements in a dose-dependent manner, while there was attenuation of the anti-parkinsonian effects of L-DOPA. These results suggest a possible role of the kappa-opioid receptors in the pathogenesis of L-DOPA-induced dyskinesia in MPTP-treated monkeys.