Involvement of the neuropeptide orphanin FQ/nociceptin in kainate and kindling seizures and epileptogenesis

Abstract

Purpose: To investigate the role of orphanin FQ/nociceptin (OFQ/N) in epilepsy, we analyzed (a) proOFQ/N (the OFQ/N precursor) and ORL-1 (the OFQ/N receptor) messenger RNA (mRNA) levels in the kainate and in the kindling models of epilepsy in the rat; and (b) seizure expression in proOFQ/N knockout mice. Methods: Epilepsy models: kainate and kindling. Northern blot analysis, radioactive in situ hybridization. Results: Increased proOFQ/N mRNA levels were found in the thalamus (reticular nucleus) after kainate administration. In contrast, ORL-1 gene expression decreased dramatically in the amygdala, hippocampus, thalamus, and cortex after kainate administration. OFQ/N knockout mice displayed reduced susceptibility to kainate-induced seizures, in that (a) lethality was reduced, (b) latency to generalized seizure onset was significantly prolonged, and (c) behavioral seizure scores were significantly reduced. Furthermore, kindling progression was delayed in OFQ/N-/- mice. Conclusions: These data indicate that limbic seizures are associated with increased OFQ/N release in multiple brain areas, causing downregulation of ORL-1 receptors and activation of OFQ/N biosynthesis in selected areas, and support the notion that the OFQ/N-ORL-1 system may play a facilitatory role in ictogenesis and in epileptogenesis.