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The Journal of Neuroscience, November 15, 2002, 22(22):10030-10038

Involvement of the Neuropeptide Nociceptin/Orphanin FQ in Kainate Seizures

Gianni Bregola^{1, 2}, Silvia Zucchini^{1, 2}, Donata Rodi^{1, 2}, Anna Binaschi^{1, 2}, Claudio D'Addario³, Daniela Landuzzi³, Rainer Reinscheid⁴, Sanzio Candeletti³, Patrizia Romualdi³, and Michele Simonato^{1, 2}

¹ Department of Clinical and Experimental Medicine, Section of Pharmacology, and ² Neuroscience Center, University of Ferrara, 44100 Ferrara, Italy, ³ Department of Pharmacology, University of Bologna, 40126 Bologna, Italy, and ⁴ Department of Pharmacology, University of California at Irvine, Irvine, California 92612

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.

Key words: epilepsy; seizure; nociceptin; opioid receptor like-1; kainate; knock-out mice

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Copyright © 2002 Society for Neuroscience  0270-6474/02/222210030-09$05.00/0

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