Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The occurrence of systematic diurnal variations in pain thresholds has been demonstrated in human. Salivary melatonin levels change following acute pain when other factors that could explain the change have been removed or controlled. Melatonin-induced analgesia is blocked by naloxone or pinealectomy. By using selective radioligands [3H]-DAMGO, [3H]-DPDPE, [3-U69593, and 3H]-nociceptin, we have shown that the bovine pinealocytes contain delta and mu, but not kappa or ORL1 opioid receptor subtypes. In the present study, by using melatonin receptor agonists (6-chloromelatonin or 2-iodo-N-butanoyl-5-methoxytryptamine) or melatonin receptor antagonist (2-phenylmelatonin), we have shown that these agents do not compete with opioid receptor subtypes. However, we observed a time-dependent release of beta-endorphin an endogenous opioid peptide, by melatonin from mouse pituitary cells in culture. Hence, it is suggested that melatonin exerts its analgesic actions not by binding to opioid receptor subtypes but by binding to its own receptors and increasing the release of beta-endorphin.
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PMID:Melatonin exerts its analgesic actions not by binding to opioid receptor subtypes but by increasing the release of beta-endorphin an endogenous opioid. 1563 42

Nociceptin activation of ORL1 (opioid receptor-like 1 receptor) has been shown to antagonize mu receptor-mediated analgesia at the supraspinal level. ORL1 and mu-opioid receptor (muR) are co-expressed in several subpopulations of CNS neurons involved in regulating pain transmission. The amino acid sequence of ORL1 also shares a high degree of homology with that of mu receptor. Thus, it is hypothesized that ORL1 and muR interact to form the heterodimer and that ORL1/muR heterodimerization may be one molecular basis for ORL1-mediated antiopioid effects in the brain. To test this hypothesis, myc-tagged ORL1 and HA-tagged muR are co-expressed in human embryonic kidney (HEK) 293 cells. Co-immunoprecipitation experiments demonstrate that ORL1 dimerizes with muR and that intracellular C-terminal tails of ORL1 and muR are required for the formation of ORL1/muR heterodimer. Second messenger assays further indicate that formation of ORL1/muR heterodimer selectively induces cross-desensitization of muR and impairs the potency by which [D-Ala(2),N-methyl-Phe(4),Gly-ol(5)]enkephalin (DAMGO) inhibits adenylate cyclase and stimulates p42/p44 mitogen-activated protein kinase (MAPK) phosphorylation. These results provide the evidence that ORL1/muR heterodimerization and the resulting impairment of mu receptor-activated signaling pathways may contribute to ORL1-mediated antiopioid effects in the brain.
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PMID:Heterodimerization of opioid receptor-like 1 and mu-opioid receptors impairs the potency of micro receptor agonist. 1574 48

The nociceptin system seems to be involved in modulation of acute nociceptive stimulation and in chronic pain processes, e.g. inflammation and neuropathy. In the present study, we examined the analgesic effect of a new opioid receptor-like (ORL1) receptor agonist, Ro64-6198, and compared it with the effect of endogenous ORL1 receptor agonist, nociceptin/orphanin FQ (N/OFQ), in a model of neuropathic pain in the rat. Ro64-6198 was injected intrathecaly (i.t.), intraplantarly (i.pl.) and subcutaneously (s.c.), and responses of neuropathic rats were measured in tactile (von Frey) and thermal (cold water) allodynia tests. Ro64-6198 did not change the pain threshold in naive animals, but exhibited antiallodynic activity in neuropathic rats. This effect was observed after i.t. and i.pl. but not after s.c. administration. Moreover, the observed antiallodynic potency of Ro64-6198 was weaker in comparison with N/OFQ after i.t. administration of either agonist, but almost equal after i.pl. injection. Selective antagonists of the ORL1 receptor, [Phe1Psi(CH2-NH)Gly2]NC(1-13)NH2 (PhePsi) and [N-Phe1]-NC(1-13)NH2 (NPhe), inhibited the antiallodynic actions of Ro64-6198 which indicated that the spinal and peripheral antinociceptive effects were mediated by ORL1 receptors. Therefore, besides spinal, also peripheral ORL1 receptors may be targeted by drugs designed for the long-term treatment of chronic pain.
Pain 2005 Jul
PMID:Spinal and local peripheral antiallodynic activity of Ro64-6198 in neuropathic pain in the rat. 1592 83

Rat/mouse hemokinin 1 (r/m HK-1) is a novel tachykinin peptide whose biological functions are not fully understood. This work was designed to observe the effects of r/m HK-1 in pain modulation at supraspinal level in mice using tail-flick test. Intracerebroventricular (i.c.v.) administration of r/m HK-1 (0.1, 0.3, 1, 3 nmol/mouse) dose-dependently induced potent analgesic effect (ED(50) = 0.2877 nmol/mouse). When r/m HK-1 co-injected (i.c.v.) with SR140333 (a selective NK(1) receptor antagonist), SR140333 could fully antagonize the analgesic effect of r/m HK-1. The maximal analgesic effect of r/m HK-1 (3 nmol/mouse) could also be reversed by naloxone (i.p., 2 mg/kg). However, i.c.v. low dose administration of r/m HK-1 (10, 3, 1 pmol/mouse) induced hyperalgesia with a "U" shape curve, which means that the maximal hyperalgesic effect appeared at 3 pmol/mouse, and this effect of r/m HK-1 could also be fully blocked by SR140333. Interestingly, [Nphe(1)]NC(1-13)NH(2), a selective opioid receptor like-1 (ORL-1) receptor antagonist, could fully reverse the maximal hyperalgesic effect of r/m HK-1 (3 pmol/mouse). In addition, when r/m HK-1 co-injected (i.c.v.) with SR48968 (a selective NK(2) receptor antagonist), SR48968 could hardly affect the nociceptive effects of r/m HK-1 either at nanomole concentration or at picomole concentration. These findings suggested that r/m HK-1 might play an important role in pain modulation at supraspinal level in mice and these effects were first elicited through the activation of NK(1) receptor, subsequently, whether activation of the classical opioid receptor or the ORL1 receptor depending on the dose of i.c.v. administration of r/m HK-1.
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PMID:Effects and mechanisms of supraspinal administration of rat/mouse hemokinin-1, a mammalian tachykinin peptide, on nociception in mice. 1610 36

The ORL1 receptor (nociceptin receptor), the fourth member of the opioid receptor family, is widely distributed throughout the central nervous system and mediates diverse physiological functions including pain, emotion, learning and memory. Nociceptin receptors are densely expressed in the suprachiasmatic nucleus, the principal pacemaker of circadian rhythms, and nociceptin inhibits light-induced phase advances (Allen et al, 1999); however, nociceptin's role in nonphotic entrainment has not been described. We used a small-molecule nociceptin receptor agonist capable of crossing the brain blood-brain barrier, and demonstrated that nociceptin acts as a nonphotic zeitgeiber. In this review, we describe a role for nociceptin in the biological clock and discuss the possibility of developing nociceptin receptor agonists for treatment of circadian rhythm disorders.
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PMID:[A role of nociceptin in the entrainment mechanism of the biological clock]. 1631 96

The peptide, nociceptin, was discovered as the endogenous ligand for the opioid-like receptor, ORL1. Since its discovery, this peptide has been shown to modulate the perception of pain, modulate feeding and produce behavioral effects in rodent models of mood disorders. Recently, the non-peptide agonist {(1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one} (Ro64-6198) of the ORL1 receptor has been reported in the literature. In the present study, we compared the distribution and potency of Ro64-6198 with nociceptin for their ability to stimulate [(35)S]-GTPgammaS binding to sections of rat brain. In initial studies, Ro64-6198 inhibited (125)I-nociceptin binding to the hORL1 receptors with a K(i) of 1.75 nM compared with 0.20 nM for nociceptin. To assess agonist potency in a whole cell assay, a cell line expressing the hORL1 receptor and G(alpha15) was created and used for calcium mobilization studies. In this assay system, Ro64-6198 increased intracellular calcium with an EC(50) of 52nM compared with 24 nM for nociceptin. Having verified the agonist properties of Ro64-6198, we then assessed the potency and distribution of ORL1 receptor activation in rat brain sections. In dose-response studies, Ro64-6198 increased [(35)S]-GTPgammaS binding to a variety of brain regions with EC(50) values ranging from 84.9 to 2,143 nM depending on the brain regions evaluated. These potencies were similar to that seen for nociceptin, but substantially lower than values established using [(125)I] nociceptin binding to the cloned human ORL1 receptor. In general, the brain distribution of agonist stimulated [(35)S]-GTPgammaS binding was similar when either Ro64-6198 or nociceptin were used. Using these techniques, we have demonstrated, for the first time that Ro64-6198 activates [(35)S]-GTPgammaS binding to rat brain sections and this compound stimulates a similar population of receptors as nociceptin.
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PMID:Distribution of nociceptin and Ro64-6198 activated [35S]-GTPgammaS binding in the rat brain. 1640 22

Nociceptin (NC), by activating its receptor, the opioid receptor-like 1 (ORL1) receptor, exerts an effect on a number of functions in the nervous system including locomotion, learning and memory, and processing of pain signals. Data on the expression of NC and ORL1 receptor in dorsal root ganglion (DRG) neurons and on its modulation after nerve injury and inflammation are controversial. We therefore sought to investigate the immunoreactivity (IR) of NC and ORL1 receptor in DRG neurons in two pain models, a pure neuropathic pain model, namely partial sciatic nerve transection (PST), and an inflammatory pain model, complete Freund's adjuvant (CFA) injection into the hindpaw. In intact DRG neurons, both NC and ORL1 receptor IR were present in mainly small- and medium-sized neurons, NC IR in 31% and ORL1 receptor IR in 33% of all neuronal profiles. Both NC and ORL1 receptor IR were upregulated 7 days after nerve injury (to 56 and 55%) and inflammation (to 53 and 48%), respectively. Activating transcription factor 3 (ATF3), a neuronal marker of nerve injury, was induced in DRG neurons 7 and 14 days after PST and 7 days after CFA injection. Double labeling with ATF3 revealed expression of NC and ORL1 receptor in intact as well as in injured primary afferent neurons. Thus, NC and the ORL1 receptor may be involved in the modulation of neuropathic and inflammatory pain at the level of the primary afferent neuron.
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PMID:Nociceptin and its receptor in rat dorsal root ganglion neurons in neuropathic and inflammatory pain models: implications on pain processing. 1693 Feb 85

Sex-related differences in the perception and modulation of pain have been reported. The present study is the first to investigate systematically whether activation of opioid receptor-like 1 receptor (ORL1) by orphanin FQ (OFQ) produces sex-specific modulation of spinal nociception and whether estrogen or testosterone contributes to these differences using the rat as an experimental animal. Two behavioral models, the NMDA and heat-induced nociceptive tests, were used to examine sex-specific modulation of spinal nociception. Intrathecal microinjection of OFQ in male, ovariectomized (OVX), and diestrous rats produced a significant antinociceptive effect on both tests. However, OFQ failed to produce antinociception in proestrous rats, the phase of the estrous cycle with the highest levels of circulating estradiol, and produced a dose-dependent effect in OVX females treated with 1 ng to 100 microg of estradiol. The antinociceptive effects of OFQ were dose dependent in male and OVX animals and were reversibly antagonized by UFP-101 ([Nphe1,Arg14,Lys15]N/OFQ(1-13)-NH2), an ORL1 receptor-selective antagonist. Interestingly, OFQ was ineffective in gonadectomized (GDX) males, whereas testosterone replacement restored the antinociceptive effect of OFQ in GDX males. We conclude that OFQ produces sex-specific modulation of spinal nociception; estrogen attenuates antinociception in the female in parallel with normal cycling of estrogen levels, and testosterone is required for the expression of antinociception in the male; thus, the sensitivity of the male to the antinociceptive effects of OFQ is not simply attributable to the intrinsically low estrogen levels in these animals.
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PMID:Activation of opioid receptor like-1 receptor in the spinal cord produces sex-specific antinociception in the rat: estrogen attenuates antinociception in the female, whereas testosterone is required for the expression of antinociception in the male. 1716 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

There has been a flurry of activity to develop agonists and antagonists for the member of the opioid receptor family, NOP receptor (also known as ORL1), in part to understand its role in pain. Modifications of a hexapeptide originally identified from a combinatorial library have led to the discovery of a high affinity hexapeptide agonist Ac-RY(3-Cl)YRWR-NH2 (Syn 1020). In the following experiments we characterized the anti-nociceptive effects of Syn 1020 in the tail-flick model of acute pain and the diabetic neuropathy model of chronic pain in mice and rats, respectively. Acute antinociception was assessed using the tail-flick assay in mice in which animals received intracerebroventricular (i.c.v.) or subcutaneous (s.c.) injections of Syn 1020 alone or with morphine and were tested for tail-flick latencies. In the chronic pain model, diabetic neuropathy was induced by injections of streptozotocin in rats. Tactile allodynia was measured, with von Frey hair filaments, following intraperitoneal (i.p.) injections of Syn 1020 or gabapentin (positive control). In mice, i.c.v. injections of Syn 1020 did not have any pro- or anti-nociceptive effects, however, Syn 1020 reversed morphine antinociception with a similar potency as N/OFQ (the natural ligand to NOP). S.c. injections of Syn 1020 in mice also produced analgesic effects. In rats, i.p, injections of Syn 1020 produced anti-allodynic effects. Thus, Syn 1020, a NOP receptor directed peptide, administered systemically has anti-nociceptive activity in both acute and chronic pain models in mice and rats respectively.
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PMID:Anti-nociceptive and anti-allodynic effects of a high affinity NOP hexapeptide [Ac-RY(3-Cl)YRWR-NH2] (Syn 1020) in rodents. 1730 10


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