The Journal of Neuroscience, September 1, 2001, 21(17):6940-6948
Nociceptin Reduces Epileptiform Events in CA3 Hippocampus via
Presynaptic and Postsynaptic Mechanisms
Melanie K.
Tallent,
Samuel G.
Madamba, and
George R.
Siggins
Department of Neuropharmacology, The Scripps Research Institute, La
Jolla, California 92037
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 Mg2+ 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
[Phe1
(CH2-NH)Gly2]NC(1-13)NH2
(1-2 µM) 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.
Key words:
nociceptin; ORL-1; epilepsy; epileptiform; slice; miniature EPSC; CA3; M-current; electrophysiology
Copyright © 2001 Society for Neuroscience 0270-6474/01/21176940-09$05.00/0
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