The
neuropeptide nociceptin/orphanin FQ (N/OFQ) has been shown to modulate neuronal excitability and
neurotransmitter release. Previous studies indicate that the
mRNA levels for the N/OFQ precursor (proN/OFQ) are increased after
seizures. However, it is unclear whether N/OFQ plays a role in seizure expression. Therefore, (1) we analyzed proN/OFQ
mRNA levels and NOP (the N/
OFQ receptor)
mRNA levels and receptor density in the
kainate model of
epilepsy, using Northern blot analysis, in situ hybridization, and receptor binding assay, and (2) we examined susceptibility to
kainate seizure in mice treated with 1-[(3R, 4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro-benzimidazol-2-one (J-113397), a selective NOP receptor antagonist, and in proN/OFQ knock-out mice. After
kainate administration, increased proN/OFQ gene expression was observed in the reticular nucleus of the thalamus and in the medial nucleus of the amygdala. In contrast, NOP
mRNA levels and receptor density decreased in the amygdala, hippocampus, thalamus, and cortex. Mice treated with the NOP receptor antagonist
J-113397 displayed reduced susceptibility to
kainate-induced
seizures (i.e., significant reduction of behavioral seizure scores). N/OFQ knock-out mice were less susceptible to
kainate seizures compared with their wild-type littermates, in that lethality was reduced, latency to
generalized seizure onset was prolonged, and behavioral seizure scores decreased. Intracerebroventricular administration of N/OFQ prevented reduced susceptibility to
kainate seizures in N/OFQ knock-out mice. These data indicate that acute limbic
seizures are associated with increased N/OFQ release in selected areas, causing downregulation of NOP receptors and activation of N/OFQ biosynthesis, and support the notion that the N/OFQ-NOP system plays a facilitatory role in
kainate seizure expression.