Vol. 284, Issue 3, 1147-1155, March 1998

Administered and Endogenously Released Kappa Opioids Decrease Pilocarpine-Induced Seizures and Seizure-Induced Histopathology¹

Suzanne B. Bausch² , Tiffany M. Esteb, Gregory W. Terman and Charles Chavkin

Departments of Pharmacology (S.B.B., T.M.E., C.C.) and Anesthesiology (G.W.T.), University of Washington, Seattle, Washington

The effects of kappa opioids on seizures and seizure-induced histopathology were investigated with the pilocarpine model of temporal lobe epilepsy. Rats treated with the kappa opioid receptor agonist U50488h before pilocarpine showed: 1) increased seizure latency; 2) decreased seizure duration; 3) decreased mossy fiber sprouting; and 4) increased hilar neuron survival when compared with rats pretreated with saline. Behavioral effects of U50488h were blocked by the kappa opioid receptor antagonist norbinaltorphimine (nBNI), whereas the changes caused by U50488h in the histological response to pilocarpine were not blocked by nBNI. Rats treated with nBNI before pilocarpine exhibited: 1) increased incidence of seizures; 2) increased mossy fiber sprouting; and 3) increased hilar neuron loss when compared with rats treated with pilocarpine alone. These changes suggest a protective role of endogenously released kappa opioids in this seizure model. The location of functional kappa opioid receptors in the rat dentate gyrus was documented electrophysiologically to enable correlation with kappa opioid effects on histopathology. The kappa selective agonist, U69593, reversibly decreased the amplitude of excitatory postsynaptic potentials in the middle molecular layer of the dentate gyrus from the ventral but not the more dorsal portion of the hippocampal formation. Thus, kappa opioids decreased the severity and incidence of behavioral seizures and secondarily decreased seizure-induced histopathology via the decreased incidence of seizures.