Nociceptin reduces epileptiform events in CA3 hippocampus via presynaptic and postsynaptic mechanisms

The opiate-like peptide nociceptin/orphanin FQ (Noc) and its receptor [opia te receptor-like receptor (ORL-1)] are highly expressed in the hippocampus. Noc has inhibitory postsynaptic actions in CA1, CA3, and the dentate and s eems to lack the disinhibitory, excitatory actions demonstrated for some op iate peptides in the hippocampus. The CA3 hippocampal region is important i n the generation of hippocampal seizures. Therefore, we tested the action o f Noc on spontaneous epileptiform activity recorded extracellularly or intr acellularly in CA3 and generated by removal of Mg2+ from the bathing soluti on or by raising extracellular K+ from 3.5 to 7.5 mM. Superfusion of Noc ro bustly depressed spontaneous bursting without desensitization. The ORL-1 an tagonist [Phe(1)Psi (CH2-NH)Gly(2)]NC(1-13) NH2 (1-2 muM) greatly attenuate d the reduction of spontaneous bursting by Noc. To characterize the cellula r mechanism of action of Noc, we recorded intracellularly from CA3 pyramida l neurons. Noc reduced EPSCs evoked by stimulating either mossy or associat ional/commissural fibers. Analysis of miniature EPSCs using whole-cell volt age-clamp recording suggests that Noc acts presynaptically to inhibit gluta mate release. This is the first demonstration of a presynaptic effect for N oc in the hippocampus. Noc also increased K+ currents in CA3 pyramidal neur ons, including the voltage-sensitive M-current. Blocking the M-current with linopirdine increased the duration of individual CA3 bursts but did not at tenuate Noc-mediated inhibition of bursting. Thus, Noc acts via multiple me chanisms to reduce excitation in CA3. However, Noc inhibition of epileptifo rm events is not dependent on augmentation of the M-current.