Effect of acute and chronic administration of U50,488 a kappa opioid receptor agonist, in 6-OHDA-lesioned rats chronically treated with levodopa

To evaluate the possible involvement of kappa opioid receptor-mediated mechanisms in levodopa-induced motor fluctuations, we have investigated the effects of U50,488, a selective kappa opioid agonist, on levodopa-induced motor alterations in rats with unilateral 6-OHDA lesion. Acute and chronic administration of U50,488 has been studied to evaluate the possible reversion or prevention of these levodopa effects. In a first set of experiments, rats were treated with levodopa (25 mg/kg with benserazide, twice daily, ip) for 22 days and, on Day 23 U50,488 (0.5, 1, or 3 mg/kg, ip) was administered immediately before levodopa. In a second set of experiments, rats were treated daily for 22 days with levodopa and U50,488 (1 or 3 mg/kg/day, ip). The duration of the rotational behavior induced by chronic levodopa decreased after 22 days (P < 0.05). Acute administration of U50,488 on Day 23 reversed this effect when low doses were administered (P < 0.05). Chronic U50,488 administration did not prevent the shortening in response duration induced by levodopa. Our results demonstrate that the kappa opioid receptor agonist U50,488 reverses but does not prevents levodopa-induced motor alterations in parkinsonian rats. These results suggest a role for kappa opioid receptor-mediated mechanisms in the pathophysiology of levodopa-induced motor response complications. These findings suggest that the stimulation of kappa opioid receptors might confer clinical benefit to parkinsonian patients under levodopa therapy suffering from motor complication syndrome. (C) 2003 Elsevier Science (USA). All rights reserved.