Mk. Tallent et al., Nociceptin reduces epileptiform events in CA3 hippocampus via presynaptic and postsynaptic mechanisms, J NEUROSC, 21(17), 2001, pp. 6940-6948
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.