Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The presence of pairs of basic amino acids within the sequence of orphanin FQ/nociceptin (OFQ/N) peptide, the endogenous ligand for the ORL1/KOR-3 receptor, has raised the possibility that processing might generate pharmacologically important truncated peptides, including OFQ/N(1-11). OFQ/N(1-11) is pharmacologically active in vivo with a potency comparable to OFQ/N. Several tyrosine-containing analogs of OFQ/N(1-11) have been synthesized and examined for antinociceptive activity. Like OFQ/N(1-11), [Tyr1]OFQ/N(1-11), [Tyr10]OFQ/N(1-11) and [IodoTyr10]OFQ/N(1-11) given supraspinally in mice were antinociceptive in the tailflick assay in mice. The tyrosine analogs showed similar potencies as OFQ/N(1-11) but longer durations of action. This response was readily reversed by the opioid antagonist naloxone despite poor affinities for these analogs at opioid receptors. Another compound, [Tyr11]OFQ/N(1-11) was highly epileptogenic, inducing naloxone-sensitive seizures in greater than 50% of the mice tested at doses comparable to those examined with the other analogs. These results indicate that it is possible to make analgesic OFQ/N(1-11) analogs. The activity of [IodoTyr10]OFQ/N(1-11) suggests that it may prove useful as a radioligand in exploring potential OFQ/N(1-11) binding sites.
 ...
PMID:Antinociceptive analogs of orphanin FQ/nociceptin(1-11). 974 1

The opiate-like peptide nociceptin/orphanin FQ (Noc) and its receptor [opiate receptor-like receptor (ORL-1)] are highly expressed in the hippocampus. Noc has inhibitory postsynaptic actions in CA1, CA3, and the dentate and seems to lack the disinhibitory, excitatory actions demonstrated for some opiate peptides in the hippocampus. The CA3 hippocampal region is important in the generation of hippocampal seizures. Therefore, we tested the action of Noc on spontaneous epileptiform activity recorded extracellularly or intracellularly in CA3 and generated by removal of Mg(2+) from the bathing solution or by raising extracellular K(+) from 3.5 to 7.5 mm. Superfusion of Noc robustly depressed spontaneous bursting without desensitization. The ORL-1 antagonist [Phe(1)Psi(CH(2)-NH)Gly(2)]NC(1-13)NH(2) (1-2 microm) greatly attenuated the reduction of spontaneous bursting by Noc. To characterize the cellular mechanism of action of Noc, we recorded intracellularly from CA3 pyramidal neurons. Noc reduced EPSCs evoked by stimulating either mossy or associational/commissural fibers. Analysis of miniature EPSCs using whole-cell voltage-clamp recording suggests that Noc acts presynaptically to inhibit glutamate release. This is the first demonstration of a presynaptic effect for Noc in the hippocampus. Noc also increased K(+) currents in CA3 pyramidal neurons, including the voltage-sensitive M-current. Blocking the M-current with linopirdine increased the duration of individual CA3 bursts but did not attenuate Noc-mediated inhibition of bursting. Thus, Noc acts via multiple mechanisms to reduce excitation in CA3. However, Noc inhibition of epileptiform events is not dependent on augmentation of the M-current.
 ...
PMID:Nociceptin reduces epileptiform events in CA3 hippocampus via presynaptic and postsynaptic mechanisms. 1151 81

The anticonvulsive activity of nociceptin, endogenous OP4 receptors agonist was investigated in pentylenetetrazole (PTZ), N-methyl D-aspartic acid (NMDA), bicucculine (BCC) and electrically evoked seizure models of experimental epilepsy. Nociceptin, at the dose of 10 nmol, suppressed the clonic seizures induced by PTZ, NMDA and BCC. [Phe1(psi)(CH2-NH)Gly2]nociceptin-(1-13)-NH2 which has been proposed to be selective antagonist OP4 receptors, did not prevent the action of nociceptin. The effect of [Phe1(psi)(CH2-NH)Gly2]nociceptin-(1-13)-NH2 on seizures induced by PTZ, NMDA and BCC was very similar to that of nociceptin. These data support the hypothesis that it possesses agonistic properties. Naloxone did not reverse the anticonvulsive action of nociceptin as well as [Phe1(psi)(CH2-NH)Gly2]nociceptin-(1-13)-NH2 which excludes the participation of opioid receptor in this action. On the other hand in the electroconvulsive model of generalized seizures, nociceptin as well as [Phe1(psi)(CH2-NH)Gly2]nociceptin-(1-13)-NH2 influenced neither the electroconvulsive threshold nor the maximal electroshock test. The data suggest that nociceptin and [Phe1(psi)(CH2-NH)Gly2]nociceptin-(1-13)-NH2 can exert anticonvulsive action. These properties depend on OP4 but not opioid receptors activation.
 ...
PMID:Nociceptin, OP4 receptor ligand in different models of experimental epilepsy. 1183 99

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.
 ...
PMID:Involvement of the neuropeptide nociceptin/orphanin FQ in kainate seizures. 1242 60

The neuropeptide nociceptin/orphanin FQ (N/OFQ) is implicated in many biological functions, including nociception, locomotor activity, stress and anxiety, drinking and food-intake. N/OFQ has also been reported to play a facilitatory role in acute kainate-induced seizures. The aim of the present study was to investigate its involvement in a chronic model of temporal lobe epilepsy, kindling epileptogenesis, using N/OFQ knock-out mice and their wild-type littermates as controls. Kindling development was retarded in N/OFQ-deficient mice, in that (compared with controls) they required a significantly greater number of stimulations and a significantly longer time in electrical seizures to reach kindling criteria. These data indicate that N/OFQ is involved in the development of kindling and that it may play a pro-epileptogenic role.
 ...
PMID:Delayed epileptogenesis in nociceptin/orphanin FQ-deficient mice. 1285 40

The opioid peptides were thought to be involved in specific types of seizures. Nociceptin/Orphanin FQ (NC) is the endogenous ligand of the nociceptin opioid peptide (NOP) receptor and may play a role in epilepsy. However, accumulated evidences indicated that NC had both anti- and pro-convulsive effects, and the direct effect of NC in modulating epilepsy in the hippocampus still remained unclear. In this study, we investigated the effect of NC on penicillin-induced seizures (PIS) in rats. Seizure model was produced by intra-hippocampus injection of penicillin in anesthetized rats. The electroencephalography (EEG) was then observed and estimated by power spectrum analysis. Pretreatment of NC (intracerebroventricular, i.c.v.) depressed PIS in a dose-dependent manner at doses of 0.055, 0.55 and 5.5 nmol in 2 microl saline, respectively. [Nphe1]Nociceptin(1-13)NH2, a selective NOP receptor antagonist reversed the effect of NC against PIS, and this antagonist was inactive to PIS itself. These results indicated that NC had a receptor-specific preventive effect against PIS.
 ...
PMID:Inhibition of nociceptin/orphanin FQ on penicillin-induced seizures in rats. 1531 6

The neuropeptide nociceptin/orphanin FQ (N/OFQ) has been suggested to play a facilitatory role in kainate seizure expression. Furthermore, mRNA levels for the N/OFQ precursor are increased following kainate seizures, while its receptor (NOP) density is decreased. These data suggest increased N/OFQ release. To obtain direct evidence that this is the case, we have developed a microdialysis technique, coupled with a sensitive radioimmunoassay, that allows measurement of N/OFQ release from the hippocampus and thalamus of awake, freely moving animals. In both these brain areas, the spontaneous N/OFQ efflux decreased by approximately 50% and 65% when Ca2+ was omitted and when tetrodotoxin was added to the perfusion medium, respectively. Perfusion of the dialysis probe with high K+ increased N/OFQ release (approximately threefold) in a Ca2+-dependent and tetrodotoxin-sensitive manner. Kainate seizures caused a twofold increase in N/OFQ release followed, within 3 h, by a return to baseline levels. Approximately 5 h after kainate, a late increase in N/OFQ release was observed. On the following day, when animals were having only low grade seizures, N/OFQ release was not significantly different from normal. These phenomena were observed with similar patterns in the hippocampus and in the thalamus. The present data indicate that acute limbic seizures are associated with increased N/OFQ release, which may prime the molecular changes described above, i.e. cause down-regulation of NOP receptors and activation of N/OFQ biosynthesis.
 ...
PMID:Kainate seizures increase nociceptin/orphanin FQ release in the rat hippocampus and thalamus: a microdialysis study. 1537 84

The effects with pretreatment with nociceptin (0.03-30nmol, i.c.v.) were evaluated on the threshold for eliciting afterdischarge (ADT), generation and spread of seizure activity and postictal depression in rats with kindling stimulation. Nociceptin produced a decrease in ADT (32-45%) in rats with partial seizures (PS, stage II-III), and an increase (61-92%) in rats with generalized seizures (GS, kindled state). Nociceptin did not modify the behavioral changes, spike frequency and duration of afterdischarge elicited at ADT in both experimental groups. In rats with GS, nociceptin enhanced postictal depression (34-44%) evaluated with a recycling paradigm. Autoradiography experiments revealed enhanced nociceptin opioid receptor (NOP) binding in medial amygdala (22-26%), frontal (21-23%) and entorhinal (27-32%) cortices, and reduced binding in the substantia nigra pars compacta (28%) and medial central gray (29%) of rats with PS. The GS group displayed significant decreased NOP binding (40-70%) in most of the brain areas evaluated. These results suggest that nociceptin facilitates ictal activity in rats with PS, whereas in animals with GS, it induces inhibitory effects on ADT and enhances the postictal period. These effects correlate with significant changes in NOP binding.
 ...
PMID:Effects of nociceptin on the spread and seizure activity in the rat amygdala kindling model: their correlations with 3H-leucyl-nociceptin binding. 1791 64

Nociceptin (N/OFQ) is involved in neuronal excitability and in certain types of seizures. Kainate-induced seizures are associated with increased N/OFQ release in the rat thalamus and hippocampus, causing down-regulation of the N/OFQ receptor (NOP). In this study, we used the neuroblastoma SH-SY5Y cell line as a model to investigate the effects of kainate on NOP receptor density and gene expression. Exposure to kainate (10-50 microM) for 3 h did not affect NOP receptor density. In contrast, a NOP Bmax down-regulation was detected in cells exposed to 10 microM kainate for both 6 and 24 h. Moreover, our data show that kainate causes a decrease in NOP mRNA levels after 3, 6, and 24 h, an effect blocked by the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). These findings show that kainate is able to affect the NOP system, both at biosynthesis and receptor density levels in SH-SY5Y cells, and that the kainate ionotropic receptor can contribute to the regulation of the NOP receptor. These data are in agreement with data obtained in vivo and provide new evidence concerning the existence of a cross-talk between NOP and kainate receptors, leading to an interplay between glutamate and N/OFQ circuits.
 ...
PMID:Kainic acid down-regulates NOP receptor density and gene expression in human neuroblastoma SH-SY5Y cells. 1828 84

There is no information concerning signal transduction mechanisms downstream of the opioid/nociceptin receptors in the human epileptic brain. The aim of this work was to evaluate the level of G-proteins activation mediated by DAMGO (a mu receptor selective peptide) and nociceptin, and the binding to mu and nociceptin (NOP) receptors and adenylyl cyclase (AC) in neocortex of patients with pharmacoresistant temporal lobe epilepsy. Patients with temporal lobe epilepsy associated with mesial sclerosis (MTLE) or secondary to tumor or vascular lesion showed enhanced [3H]DAMGO and [3H]forskolin binding, lower DAMGO-stimulated [35S]GTPgammaS binding and no significant changes in nociceptin-stimulated G-protein. [3H]Nociceptin binding was lower in patients with MTLE. Age of seizure onset correlated positively with [3H]DAMGO binding and DAMGO-stimulated [35S]GTPgammaS binding, whereas epilepsy duration correlated negatively with [3H]DAMGO and [3H]nociceptin binding, and positively with [3H]forskolin binding. In conclusion, our present data obtained from neocortex of epileptic patients provide strong evidence that a) temporal lobe epilepsy is associated with alterations in mu opioid and NOP receptor binding and signal transduction mechanisms downstream of these receptors, and b) clinical aspects may play an important role on these receptor changes.
 ...
PMID:Temporal lobe epilepsy causes selective changes in mu opioid and nociceptin receptor binding and functional coupling to G-proteins in human temporal neocortex. 1957


1 2 Next >>