The opiate-like peptide nociceptin/orphanin FQ (Noc) and its receptor [opiate receptor-like receptor (ORL-1)] are highly expressed in the hippocampus. Noc has inhibitory postsynaptic actions in CA1, CA3, and the dentate and seems to lack the disinhibitory, excitatory actions demonstrated for some opiate peptides in the hippocampus. The CA3 hippocampal region is important in the generation of hippocampal seizures. Therefore, we tested the action of Noc on spontaneous epileptiform activity recorded extracellularly or intracellularly in CA3 and generated by removal of Mg(2+) from the bathing solution or by raising extracellular K(+) from 3.5 to 7.5 mm. Superfusion of Noc robustly depressed spontaneous bursting without desensitization. The ORL-1 antagonist [Phe(1)Psi(CH(2)-NH)Gly(2)]NC(1-13)NH(2) (1-2 microm) greatly attenuated the reduction of spontaneous bursting by Noc. To characterize the cellular mechanism of action of Noc, we recorded intracellularly from CA3 pyramidal neurons. Noc reduced EPSCs evoked by stimulating either mossy or associational/commissural fibers. Analysis of miniature EPSCs using whole-cell voltage-clamp recording suggests that Noc acts presynaptically to inhibit glutamate release. This is the first demonstration of a presynaptic effect for Noc in the hippocampus. Noc also increased K(+) currents in CA3 pyramidal neurons, including the voltage-sensitive M-current. Blocking the M-current with linopirdine increased the duration of individual CA3 bursts but did not attenuate Noc-mediated inhibition of bursting. Thus, Noc acts via multiple mechanisms to reduce excitation in CA3. However, Noc inhibition of epileptiform events is not dependent on augmentation of the M-current.