Involvement of the neuropeptide orphanin FQ/nociceptin in kainate and kindling seizures and epileptogenesis.
OBJECTIVE
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.
Department of Experimental and Clinical medicine, Section of Pharmacology, University of Ferrara, via Fossaro di Mortara 17-19, 44100 Ferrara, Italy. bg@unife.it
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Bregola
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Zucchini
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Frigati
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Candeletti
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Romualdi
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Reinscheid
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Simonato
D000818:Animals; D004827:Epilepsy / Q000139:chemically induced* / Q000209:etiology* / Q000235:genetics; D018690:Excitatory Amino Acid Agonists; D015870:Gene Expression; D007608:Kainic Acid; D007696:Kindling, Neurologic; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D018847:Opioid Peptides / Q000235:genetics / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000235:genetics; D012640:Seizures / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D018690:Excitatory Amino Acid Agonists; D007608:Kainic Acid; D018847:Opioid Peptides; D011498:Protein Precursors; D012333:RNA, Messenger; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C119224:pronociceptin