The kappa opioid agonist U50,488 potentiates 6-hydroxydopamine-induced neurotoxicity on dopaminergic neurons

Male Sprague-Dawley rats received an acute (0.5 mg/kg) or subacute (0.5 mg/kg, twice at day, for 7 days) administration of U50,488, receiving the last dose 30 min before intrastriatal 6-OHDA administration. Acute or subacute U50,488 pretreatment potentiated the 6-OHDA-induced decrease in the number of nigral tyrosine hydroxylase immunoreactive neurons (P < 0.05). Acute U50,488 pretreated animals showed a tendency, although not statistically significant to increase striatal mRNA encoding for enkephalin (PPE mRNA). Subacute U50,488 significantly potentiated the increase in PPE mRNA induced by 6-OHDA (P < 0.05). The present results show a neurotoxic effect of the kappa agonist U50,488 on dopaminergic neurons in rats with a striatal lesion induced by 6-OHDA. This neurotoxic effect is associated to an increase in striatal PPE mRNA levels, suggesting that an increase in the indirect pathway activity and consequently an increase in the activity of the subthalamo-nigral pathway might be involved in this phenomenon.