Roles of opioid peptides in the regulation of hippocampal excitability are under intensive study after the discovery of endogenous opiates in the brain. Intraventricular administration of opioid peptides elicited epileptiform discharges and wet dog shakes (WDS) in rats, however, no behavioral convulsion was observed. We have shown that a single unilateral injection of specific mu opioid receptor agonists into the ventral hippocampus, but not into the dorsal hippocampus or other brain regions, resulted in a dose-dependent increase in the frequency of convulsions and wet dog shakes. We also demonstrated that these opioid-induced behavioral changes were mediated exclusively by mu but not delta or kappa opioid receptors in the ventral hippocampus. The disparity between the ventral and dorsal hippocampus in seizure sensitivity to mu opioid receptor agonists could be due to differences either extrinsic or intrinsic to the hippocam- pus. The latter possibility was tested in this study with an in vitro method using dorsal and ventral hippocampal slices from the same rat. Paired dorsal and ventral hippocampal slices were perfused with [NMe-Phe3-D-Pro4]morphiceptin (PLO17), a specific mu opioid receptor agonist. Application of 0.05 (mu)M P1017 produced triggered and spontaneous bursting in 20% of ventral hippocampal slices, but no such effect was observed in dorsal hippocampal slices. At 0.5 (mu)M PLO17, 80% of ventral slices developed spontaneous bursting, whereas only 10% of dorsal slices had spontaneous bursting. The addition of 0.1 (mu)M naloxone prior to or after PLO17 inhibited the triggered response and reduced the frequency of the spontaneous bursting. These results suggest that the ventral hippocampus has a higher susceptibility to PL07-induced epileptiform bursting, and this effect is mediated, at least in part, through mu opioid receptors. Further studies are planned, by using hippocampal primary cell culture as a tool, to determine molecular mechanisms of opiate-induced excitability in the hippocampus. This project will be terminated September 30, 1990.
