Orphanin-FQ/nociceptin inhibits kindling epileptogenesis and enhances hippocampal feed-forward inhibition

The role of Orphanin-FQ/nociceptin in synaptic plasticity was assessed by i ts potency in modulating kindling epileptogenesis in vivo, and feed-forward inhibition in hippocampal recordings in vitro. In addition, a specific rab bit antiserum against this peptide was obtained and the immunohistochemical distribution of nociceptin was determined in rat brain slices. After the e stablishment of kindling epilepsy, by daily electrical stimulation of the p iriform cortex, the i.c.v. injection of nociceptin, 20 min before the kindl ing stimulation, was not able to block the generation of the generalized se izures, nor to alter their duration. However, the i.c.v. injection of nocic eptin, 20 min before each stimulation along the kindling process, depressed its development in a dose-dependent manner. This effect was specific since the nociceptin antagonist [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2, but not the br oad-spectrum opiate antagonist, naloxone, was able to completely block noci ceptin actions. The inhibitory role of nociceptin was assessed by in vitro recordings from entorhinal cortex-hippocampal slices. By single pulses appl ied over the Schaffer collaterals, we found that synaptic transmission was facilitated onto CA1, but using a paired-pulse protocol, xe found that noci ceptin potentiated feedforward inhibition. The immunohistochemical data sho w that nociceptin is expressed in limbic cortical regions, including the pi riform cortex and the hippocampus. Our results demonstrate that nociceptin exerts a modulatory role in limbic excitability and Suggest that it provides an inhibitory control in the deve lopment of epilepsy by possibly inhibiting the spread of excitation through the system, by favoring feed-forward inhibition. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.