Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nociceptin/orphanin FQ (N/OFQ) is an endogenous opioid-like heptadecapeptide that plays an important role in a variety of physiological functions. N/OFQ and its receptor opioid receptor-like orphan receptor-1 are abundant in the diagonal band of Broca (DBB), a basal forebrain nucleus where the loss of cholinergic neurons is linked to memory and spatial learning deficits. In the whole animal, central injections of N/OFQ have been shown to disrupt spatial learning. In this study, we investigated the basis for these behavioral observations by examining the cellular effects of N/OFQ on chemically identified DBB neurons. Whole cell patch-clamp recordings were performed on enzymatically dissociated DBB neurons. Under voltage-clamp conditions, bath application of N/OFQ (10 pM-1 microM) resulted in a dose-dependent depression of whole cell currents. Single cell reverse transcription-polymerase chain reaction analysis identified cholinergic and fewer GABAergic cells to be N/OFQ-responsive. [Nphe(1)]nociceptin-(1-13)-NH(2) and CompB (J-113397) antagonized the N/OFQ response, but both compounds also displayed partial agonist activity. Using a combination of channel blockers we determined that the effects of N/OFQ were mediated via a suite of Ca(2+) (N- and L-type) and Ca(2+)-dependent K(+) (iberiotoxin-sensitive) conductances. In addition, biophysical analysis of voltage subtraction protocols revealed that N/OFQ reduces transient outward and the delayed rectifier K(+) currents. Because N-type and L-type Ca(2+) channels are important in the context of neurotransmitter release, our observations indicate that N/OFQ inhibition of Ca(2+)-dependent conductances in cholinergic neurons would be expected to result in depression of acetylcholine release, which may explain the behavioral actions of N/OFQ in the brain.
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PMID:Nociceptin/orphanin FQ modulation of ionic conductances in rat basal forebrain neurons. 1223 50

Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the NOP receptor, regulates several central functions such as pain transmission, learning and memory, fear and anxiety and feeding and locomotor activity. It has been recently reported that NOP receptor antagonists induce antidepressant-like effects in the mouse forced swimming test (FST), i.e. reduce immobility time. This assay was used in the present study for further investigating the involvement of the NOP receptor in depression states. In male Swiss mice, intracerebroventricular injection (i.c.v) of the novel NOP receptor antagonist, UFP-101 (1-10 nmol) dose-dependently reduced the immobility time (control 192 +/- 14 s, UFP-101 91 +/- 15 s). The effect of 3 or 10 nmol UFP-101 was fully or partially reversed, respectively, by the coadministration of 1 nmol N/OFQ, which was inactive per se. NOP receptor knockout mice showed a reduced immobility time compared with their wild-type littermates (wild-type 215 +/- 10 s, knockout 143 +/- 12 s). Moreover, i.c.v. injected UFP-101 (10 nmol) significantly reduced immobility time in wild-type mice but not in NOP receptor knockout animals. In conclusion, these results, obtained using a combined pharmacological and genetic approach, indicate that blockade of the N/OFQ-NOP receptor signalling in the brain produces antidepressant-like effects in the mouse FST. These findings support the NOP receptor as a candidate target for the development of innovative antidepressant drugs.
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PMID:Blockade of nociceptin/orphanin FQ-NOP receptor signalling produces antidepressant-like effects: pharmacological and genetic evidences from the mouse forced swimming test. 1275 99

We have previously shown that N/OFQ, the endogenous peptide ligand for the 'opioid-like' NOP receptor, inhibits cough in guinea pigs and cats. In the present study we sought to continue our characterization of the cough-suppressant effects of NOP stimulation by profiling the pulmonary and antitussive effects of a novel non-peptide NOP agonist, Ro-64-6198, in guinea pigs. In receptor-binding assays, we confirmed that Ro-64-6198 selectively binds to NOP receptors over other opioid receptors. The Ki values for Ro-64-6198 at NOP, MOP, KOP and DOP receptors was 0.3, 36, 214 and 3,787 nmol/l, respectively. In GTPgammaS-binding assays, Ro-64-6198 displayed >900-fold functional selectivity at NOP relative to MOP receptors. We evaluated the effects of Ro-64-6198 (3 and 10 micromol/l) in isolated guinea pig nodose ganglia cells on the increases in intracellular Ca2+ concentration evoked by capsaicin stimulation (1 x 10(-8)-1 x 10(-6) mol/l). Similar to previously reported data with N/OFQ, Ro-64-6198 (3 and 10 micromol/l) significantly attenuated Ca2+ responses in nodose ganglia cells produced by exposure to capsaicin. The effect of Ro-64-6198 (3 micromol/l) on capsaicin-induced intracellular Ca2+ responses was blocked by the NOP antagonist, J113397 (3 micromol/l). In guinea pig in vivo studies, aerosolized capsaicin (10-300 micromol/l) produced a dose-dependent increase in cough number. Ro-64-6198 given i.p. significantly inhibited cough due to capsaicin (300 micromol/l) exposure. In a duration study we found that the maximum antitussive effect (42 +/- 8% inhibition) of Ro-64-6198 (3 mg/kg) was observed at 1 h after i.p. administration. Also at 1 h after administration, Ro-64-6198 (0.003-3.0 mg/kg, i.p.) produced a dose-dependent inhibition of cough. The antitussive effect of Ro-64-6198 (3 mg/kg, i.p.) was blocked by J113397 (12 mg/kg, i.p.) but not by the classical opioid antagonist naltrexone (10 mg/kg, i.p.). Although the antitussive action of Ro-64-6198 may be mediated by a central and/or a peripheral site of action, we hypothesize that selective oral NOP agonists that do not penetrate the blood-brain barrier may provide a novel approach for the treatment of cough. Moreover, because these drugs do not interact at MOP receptors, they may be devoid of codeine-like side effects such as respiratory depression, sedation, constipation or proclivities for addictive liabilities.
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PMID:Antitussive profile of the NOP agonist Ro-64-6198 in the guinea pig. 1516 96

Environmental synchronization of the endogenous mammalian circadian rhythm involves glutamatergic and GABAergic neurotransmission within the hypothalamic suprachiasmatic nucleus (SCN). The neuropeptide nociceptin/orphanin FQ (N/OFQ) inhibits light-induced phase shifts, evokes K(+)-currents and reduces the intracellular Ca(2+) concentration in SCN neurons. Since these effects are consistent with a modulatory role for N/OFQ on synaptic transmission in the SCN, we examined the effects of N/OFQ on evoked and spontaneous excitatory and inhibitory currents in the SCN. N/OFQ produced a consistent concentration-dependent inhibition of glutamate-mediated excitatory postsynaptic currents (EPSC) evoked by optic nerve stimulation. N/OFQ did not alter the amplitude of currents induced by application of (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or N-methyl-d-aspartate (NMDA) nor the amplitude of miniature EPSC (mEPSC) consistent with a lack of N/OFQ effect on postsynaptic AMPA or NMDA receptors. N/OFQ significantly reduced the mEPSC frequency. The inhibitory actions of N/OFQ were blocked by omega-conotoxin GVIA, an N-type Ca(2+)channel antagonist and partially blocked by omega-agatoxin TK, a P/Q type Ca(2+) channel blocker. These data indicate that N/OFQ reduces evoked EPSC, in part, by inhibiting the activity of N- and P/Q-type Ca(2+) channels. In addition, N/OFQ produced a consistent reduction in baseline Ca(2+) levels in presynaptic retinohypothalamic tract terminals. N/OFQ also inhibited evoked GABA(A) receptor-mediated inhibitory postsynaptic currents (IPSC) in a concentration dependent manner. However, N/OFQ had no effect on currents activated by muscimol application or on the amplitude of miniature IPSC (mIPSC) and significantly reduced the mIPSC frequency consistent with an inhibition of GABA release downstream from Ca(2+) entry. Finally, N/OFQ inhibited the paired-pulse depression observed in SCN GABAergic synapses consistent with a presynaptic mechanism of action. Together these results suggest a widespread modulatory role for N/OFQ on the synaptic transmission in the SCN.
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PMID:Nociceptin/orphanin FQ (N/OFQ) inhibits excitatory and inhibitory synaptic signaling in the suprachiasmatic nucleus (SCN). 1585 1

The opioid-like neuropeptide nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are expressed in the substantia nigra (SN), a brain area containing dopamine neurons that degenerate in Parkinson's disease. Endogenous N/OFQ facilitates nigral glutamate release and inhibits nigrostriatal dopamine transmission and motor behavior. Here, we present evidence suggesting that endogenous N/OFQ may contribute to Parkinson's disease. Pharmacological blockade of the SN N/OFQ-NOP receptor system attenuated parkinsonian-like akinesia/hypokinesia in 6-hydroxydopamine hemilesioned or haloperidol-treated rats, whereas deletion of the NOP receptor gene conferred mice partial protection from haloperidol-induced motor depression. The antiparkinsonian action of NOP receptor antagonists was associated with reduction of glutamate release in the SN. In 6-hydroxydopamine hemilesioned rats, enhancement of N/OFQ expression and release was detected in the lesioned compared with the unlesioned SN, indicating that parkinsonism may be associated with overactivation of the N/OFQ-NOP receptor system in the SN. Finally, deletion of the N/OFQ gene conferred mice partial protection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of SN dopamine neurons. Based on these data, we propose that NOP receptor antagonists may represent a novel approach for combined (symptomatic and neuroprotective) therapy of Parkinson's disease.
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PMID:Blockade of nociceptin/orphanin FQ transmission attenuates symptoms and neurodegeneration associated with Parkinson's disease. 1623 64

Many studies point toward the nociceptin/orphanin FQ (N/OFQ) and the N/OFQ peptide receptor (NOP) as targets for the development of innovative drugs for treating affective disorders. It has been reported that the activation of NOP receptors produces anxiolytic-like effects in rodents in a large series of behavioral assays, i.e., elevated plus maze, light-dark aversion, operant conflict, fear-potentiated startle, pup ultrasonic vocalizations, and hole board tests. In contrast, the blockade of N/OFQ signaling obtained with NOP-selective antagonists promotes antidepressant-like effects in the forced swimming and tail suspension tests. In these assays, N/OFQ is inactive per se, but reverses the antidepressant-like effects of NOP antagonists. NOP receptor knockout mice show an antidepressant-like phenotype, and NOP antagonists are inactive in these animals. Thus, the activation of the NOP receptor seems to evoke anxiolytic-like effects while its blockade antidepressant-like effects. This appears to be a rather unique behavioral profile since the activation or the blockade of a given neuropeptide receptor produces, in most of the cases, both antidepressant- and anxiolytic-like effects. This particular behavioral profile, the possible mechanisms of action, and the therapeutic potential of NOP receptor ligands for the treatment of depression and anxiety disorders are discussed in this review article.
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PMID:Antidepressant- and anxiolytic-like effects of nociceptin/orphanin FQ receptor ligands. 1649 87

Almost 10 years after the discovery of Orphanin FQ / Nociceptin (OFQ/N) a large number of synthetic small molecule agonists and antagonists have been developed and tested in various physiological assays. Together with the academic work on the physiological functions of OFQ/N, we now have compelling evidence that this neuropeptide system might represent a valuable target for the development of drugs treating a variety of psychiatric disorders. Most prominently, the anti-stress and anxiolytic effects of OFQ/N agonists have been investigated although clinical trials have not yet been launched. Other possible applications of OFQ/N agonists and antagonists include treatment of depression, anorexia and rewarding aspects of drug addiction. This paper will summarize current developments and highlight the scientific achievements that have been made to elucidate the functions of OFQ/N with respect to psychiatric disorders.
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PMID:The Orphanin FQ / Nociceptin receptor as a novel drug target in psychiatric disorders. 1661 Oct 94

The advance of functional genomics revealed the superfamily of G-protein coupled receptors (GPCRs). Hundreds of GPCRs have been cloned but many of them are orphan GPCRs with unidentified ligands. The first identified orphan GPCR is the opioid receptor like orphan receptor, ORL1. It was cloned in 1994 during the identification of opioid receptor subtypes and was de-orphanized in 1995 by the discovery of its endogenous ligand, nociceptin or orphanin FQ (N/OFQ). This receptor was renamed as N/OFQ peptide (NOP) receptor. Several selective ligands acting at NOP receptors or other anti-N/OFQ agents have been reported. These include N/OFQ-derived peptides acting as agonists (cyclo[Cys(10),Cys(14)]N/OFQ, [Arg(14), Lys(15)]N/OFQ, [pX]Phe(4)N/OFQ(1-13)-NH(2), UFP-102, [(pF)Phe(4),Aib(7), Aib(11),Arg(14),Lys(15)]N/OFQ-NH(2)) or antagonists (Phe(1)psi(CH(2)-NH)Gly(2)]N/OFQ(1-13)-NH(2), [Nphe(1)]N/OFQ(1-13)-NH(2), UFP-101, [Nphe(1), (pF)Phe(4),Aib(7),Aib(11),Arg(14),Lys(15)]N/OFQ-NH(2)), hexapeptides, other peptide derivatives (peptide III-BTD, ZP-120, OS-461, OS-462, OS-500), non-peptide agonists (NNC 63-0532, Ro 64-6198, (+)-5a compound, W-212393, 3-(4-piperidinyl)indoles, 3-(4-piperidinyl) pyrrolo[2,3-b]pyridines) and antagonists (TRK-820, J-113397, JTC-801, octahydrobenzimidazol-2-ones, 2-(1,2,4-oxadiazol-5-yl)-1 H-indole, N-benzyl-D-prolines, SB-612111), biostable RNA Spiegelmers specific against N/OFQ, and a functional antagonist, nocistatin. Buprenorphine and naloxone benzoylhydrazone are two opioid receptor ligands showing high affinity for NOP receptors. NOP receptor agonists might be beneficial in the treatment of pain, anxiety, stress-induced anorexia, cough, neurogenic bladder, edema, drug dependence, and, less promising, in cerebral ischemia and epilepsy, while antagonists might be of help in the management of pain, depression, dementia and Parkinsonism. N/OFQ is also involved in cardiovascular, gastrointestinal and immune regulation. Altered plasma levels of N/OFQ have been reported in patients with various pain states, depression and liver diseases. This review summarizes the pharmacological characteristics of, and studies with, the available NOP receptor ligands and their possible clinical implications.
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PMID:Nociceptin/orphanin FQ peptide receptors: pharmacology and clinical implications. 1726 36

Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the opioid receptor-like-1 (ORL-1) orphan receptor, which is responsible for inhibition of delayed rectifier potassium current (I(K)). But its mechanism of N/OFQ acting on I(K) is not clear and whether PKC is involved in the modulation of this processing is still unknown. Whole-cell patch-clamp recordings were performed in acutely dissociated rat parietal cortical neurons. Bath application of N/OFQ (10 nM-10 microM) resulted in a dose-dependent depression of I(K) with partially recovery on washout. Furthermore, we investigated the role of PKC in the inhibition of I(K) by N/OFQ. Chelerythrine, an inhibitor of PKC, attenuated the inhibition of N/OFQ on I(K). On the contrary, PDBu, an activator of PKC, augmented N/OFQ-evoked responses. The present study suggested that N/OFQ inhibited I(K) and PKC was involved in N/OFQ-evoked response in acutely dissociated rat cerebral parietal cortical neurons.
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PMID:Effects of PKC on inhibition of delayed rectifier potassium currents by N/OFQ. 1738 98

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.
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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


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