Involvement of the neuropeptide nociceptin/orphanin FQ in kainate seizures.
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.
Bregola
Gianni
G
Department of Clinical and Experimental Medicine, Section of Pharmacology, University of Ferrara, 44100 Ferrara, Italy.
Zucchini
Silvia
S
Rodi
Donata
D
Binaschi
Anna
A
D'Addario
Claudio
C
Landuzzi
Daniela
D
Reinscheid
Rainer
R
Candeletti
Sanzio
S
Romualdi
Patrizia
P
Simonato
Michele
M
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism; D006720:Homozygote; D007276:Injections, Intraventricular; D007608:Kainic Acid; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009292:Narcotic Antagonists; D018847:Opioid Peptides / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D010880:Piperidines / Q000494:pharmacology; D016548:Prosencephalon / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*; D013788:Thalamus / Q000737:chemistry / Q000378:metabolism; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D001562:Benzimidazoles; D007608:Kainic Acid; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010880:Piperidines; D012333:RNA, Messenger; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C402921:J 113397