ADMINISTERED AND ENDOGENOUSLY RELEASED KAPPA-OPIOIDS DECREASE PILOCARPINE-INDUCED SEIZURES AND SEIZURE-INDUCED HISTOPATHOLOGY

The effects of kappa opioids on seizures and seizure-induced histopath ology were investigated with the pilocarpine model of temporal lobe ep ilepsy. Rats treated with the kappa opioid receptor agonist U50488h be fore pilocarpine showed: 1) increased seizure latency; 2) decreased se izure duration; 3) decreased mossy fiber sprouting; and 4) increased h ilar neuron survival when compared with rats pretreated with saline. B ehavioral effects of U50488h were blocked by the kappa opioid receptor antagonist norbinaltorphimine (nBNI), whereas the changes caused by U 50488h in the histological response to pilocarpine were not blocked by nBNI. Rats treated with nBNI before pilocarpine exhibited: 1) increas ed incidence of seizures; 2) increased mossy fiber sprouting; and 3) i ncreased hilar neuron loss when compared with rats treated with piloca rpine alone. These changes suggest a protective role of endogenously r eleased kappa opioids in this seizure model. The location of functiona l kappa opioid receptors in the rat dentate gyrus was documented elect rophysiologically to enable correlation with kappa opioid effects on h istopathology. The kappa selective agonist, U69593, reversibly decreas ed the amplitude of excitatory postsynaptic potentials in the middle m olecular layer of the dentate gyrus from the ventral but not the more dorsal portion of the hippocampal formation. Thus, kappa opioids decre ased the severity and incidence of behavioral seizures and secondarily decreased seizure-induced histopathology via the decreased incidence of seizures.