ROLES OF OPIOID PEPTIDES IN THE REGULATION OF HIPPOCAMPAL EXCITABILITY

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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. We have shown that injection of specific mu receptor agonist(NMe-Phe3-D-Pro4)-morphiceptin (PL017) into the ventral hippocampus produced behavioral convulsions and WDS in rats. The purpose of this study was to further investigate the role of other hippocampal opioid receptor subtypes, delta and kappa, on the expression of convulsions and WDS. Selective mu agonist, PL017 or (D-Ala2-N-methyl-Phe3-Gly5-ol)-enkephalin, produced convulsions and WDS when unilaterally injected into the ventral hippocampus. The mixed mu-delta agonist (D-Ala2,D-Leu5)- enkephalin (DADLE) also elicited such behavioral changes, but its effect was less potent than the mu agonists. Similar treatment with the selective delta agonist, (D-Pen2,5)enkephalin or the elective kappa agonists, U-50488H, dynorphin-A amide or dynorphin A(1-8), did not produce convulsions or WDS. DADLE-induced convulsions and WDS were antagonized by mu receptor antagonist, beta-funaltrexamine, but not by selective delta receptor antagonist, ICI-174864. These results demonstrate that opioid- induced convulsions and WDS in rats are mediated exclusively by mu but not delta or kappa opioid receptors in the ventral hippocampus. The injection of a high dose of PL017 into the dorsal hippocampus or other brain regions such as frontal cortex, striatum and amygdala did not produce convulsions or WDS. These findings suggest that the ventral hippocampus is an important site for the expression of opioid-induced convulsions and WDS. Further studies are planned, by using hippocampal slice as a tool, to determine the response of dorsal against ventral hippocampus on opioid peptides induced excitation. In vitro release of GABA will be determined to test the hypothesis that opiates induced excitability in hippocampus may be mediated through the inhibition of GABA release.