Kappa opioid receptor agonists suppress absence seizures in WAG/Rij rats

Abstract

Involvement of the kappa opioid receptor in the regulation of epileptic activity was studied in WAG/Rij rats, a genetic model of absence epilepsy. I.c.v. administration of the kappa agonists U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide), U69,593 (5 alpha, 7 alpha, 8 beta)-(-)-N-methyl-(1-pyrrolidinyl)-1- oxaspiro(4,5)dec-8-yl)benzeneacetamide) or PD117,302 ((+/-)-trans-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl]benzo[b]thiophene-4-acetamide), 50 and 150 micrograms/5 microliter each, dose-dependently decreased the number and mean duration of spike wave discharges (SWD). Peripheral administration of U50,488H (10 and 30 mg/kg s.c.) also attenuated the seizure activity in this model. The specific kappa opioid receptor antagonist nor-binaltorphimine (Nor-BNI, 10 micrograms/5 microliters i.c.v., 18 h before EEG registration) moderately increased the number of SWD, which suggests that endogenous opioids acting through kappa receptors may tonically inhibit the seizure activity in these rats. In addition, the enhancement of an absence-like seizure activity induced by the specific mu opioid receptor agonist D-Ala2-N-methyl-Phe4-Gly5-ol-enkephalin (DAMGO, 0.7 microgram/5 microliters i.c.v.) was also attenuated in rats pretreated with U50,488H, U69,593 or PD117,302. These data indicate that activation of the kappa opioid receptor exerts an inhibitory effect on absence-like seizure activity in WAG/Rij rats.