Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study investigated the modulatory actions of nociceptin/orphanin FQ on excitatory glutamatergic transmission in spinal dorsal horn. In transverse spinal cord slices with an attached dorsal root, mono- and polysynaptic A delta-fibre-evoked extracellular field potentials were recorded from superficial dorsal horn. Nociceptin/orphanin FQ showed bidirectional effects on monosynaptic transmission with a potentiation at lower concentrations (100-300 nM) and a dose-dependent depression at higher concentrations (1-3 microM). The polysynaptic field potential was dose-dependently depressed by nociceptin/orphanin FQ (100 nM-3 microM). None of the actions of nociceptin/orphanin FQ was reversed by the non-specific opioid receptor antagonist naloxone, the N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosphonovaleric acid or the peptide nocistatin. The bidirectional actions of nociceptin/orphanin FQ on the monosynaptic field potential may provide an in vitro model for the bidirectional actions of nociceptin/orphanin FQ in behavioural studies showing hyperalgesia at low doses of intrathecal nociceptin/orphanin FQ and analgesia at higher doses.
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PMID:Bidirectional actions of nociceptin/orphanin FQ on A delta-fibre-evoked responses in rat superficial spinal dorsal horn in vitro. 1173 Nov 1

A novel member of the opioid related receptor family, the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor was identified and demonstrated to be involved in many physiological functions including pain regulation. [Nphe(1)]N/OFQ-(1-13)-NH(2) (Nphe) is a novel peptide antagonist of NOP receptors, developed using peripheral preparations. We have quantitatively investigated the interaction of Nphe with N/OFQ, the endogenous ligand of NOP receptors, in the midbrain ventrolateral periaqueductal gray (PAG), a crucial brain region for N/OFQ-induced reversal of opioid analgesia, using the patch-clamp recording technique in brain slices. N/OFQ concentration-dependently activated an inwardly rectifying K(+) current in response to hyperpolarization ramps from -60 to -140 mV. Nphe concentration-dependently attenuated the K(+) current activated by N/OFQ without changing its reversal potential. The presence of Nphe right-shifted the concentration-response curve to N/OFQ in a parallel manner. The Schild plot analysis yielded a slope of 1.16 and a pA(2) value of 6.64 that is similar to those obtained in peripheral preparations. At concentrations up to 3 microM, Nphe affected neither the membrane current per se, nor the inwardly rectifying K(+) current activated by [D-Ala(2), N-Me-Phe(4),Gly-ol(5)]-enkephalin or baclofen, a mu-opioid and GABA(B) receptor agonist, respectively. It is concluded that Nphe acts as a pure, selective and competitive antagonist at native NOP receptors of ventrolateral PAG neurons.
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PMID:[Nphe(1)]N/OFQ-(1-13)-NH(2) is a competitive and selective antagonist at nociceptin/orphanin FQ receptors mediating K(+) channel activation in rat periaqueductal gray slices. 1180 21

Nociceptin is a preferred endogenous ligand for the orphan opioid receptor-like 1 (ORL1) receptor. Central administration of nociceptin showed various pharmacological effects on analgesia, cardiovascular and renal responses, food intake, and so on. In the present study, we investigated the effect of nociceptin injected into the central nervous system (CNS) on gastric acid secretion in the perfused stomach of urethane-anesthetized rats. Injection of nociceptin (0.55-5.52 nmol per rat) into the fourth cerebroventricle stimulated gastric acid secretion and the secretion was inhibited in atropine-treated (1 mg/kg, i.v.) and vagotomized rats. The secretion induced by nociceptin (1.65 nmol) was not inhibited by the central injection of naloxone (275 nmol, a non-selective antagonist of opioid receptors). The secretion was significantly inhibited by the central injection of [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin-(1-13)-NH(2) ([F/G]nociceptin-(1-13), 0.21 nmol, an antagonist of ORL1 receptor), although [F/G]nociceptin-(1-13) alone at higher doses (2.10 and 7.31 nmol) markedly stimulated gastric acid secretion. In the 0-40 min period, the secretion induced by nociceptin was inhibited at least partially by CompB (68.8 nmol, a nonpeptidic antagonist of ORL1 receptor). Injection of nociceptin (5.52 nmol) into the lateral cerebroventricle also stimulated the secretion. Injection of nociceptin did not modify gastric acid secretion stimulated by 2-deoxy-D-glucose (200 mg/kg, i.v.). In conclusion, nociceptin injected into the CNS stimulated gastric acid secretion in rats via the ORL1 receptors and through mechanisms involving the vagus nerve.
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PMID:Gastric acid secretion stimulated by centrally injected nociceptin in urethane-anesthetized rats. 1200 27

Nociceptin can induce spinal analgesia in rats. Here, we tested the ability of nociceptin to inhibit the nociceptive behavior (biting, scratching, licking) induced by intrathecal administration of N-methyl-D-aspartate (4 microg) or the tachykinin NK(1) receptor agonist, septide (0.5 microg), in rats. Intrathecal nociceptin (3-30 nmol) did not modify the NMDA-induced behavior. However, coadministration of nociceptin (1-10 nmol) inhibited the septide-induced excitatory response. This inhibition was unaffected by systemic (10 mg/kg) or intrathecal (30 nmol) administration of naloxone, but intrathecal coadministration of the ORL1 (opioid receptor-like type 1) receptor antagonist [Nphe(1)]nociceptin-(1-13)-NH(2) (30-90 nmol) prevented it, suggesting the involvement of ORL1 receptors.
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PMID:Spinal nociceptin inhibits septide but not N-methyl-D-aspartate-induced nociceptive behavior in rats. 1206 97

A novel opioid receptor family, the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptors, has been identified to be involved in many physiological functions including pain regulation. CompB (also known as J-113397) is the first non-peptide antagonist of NOP receptors. Using the patch-clamp recording technique in brain slices, we have quantitatively studied the interactions of CompB with N/OFQ at native NOP receptors of ventrolateral neurons of the midbrain periaqueductal gray (PAG), a crucial region for N/OFQ-induced reversal of opioid analgesia. N/OFQ concentration-dependently activated inwardly rectifying K(+) channels in response to hyperpolarization ramps from -60 to -140 mV. CompB attenuated the magnitude but not the reversal potential of the K(+) current activated by N/OFQ in a concentration-dependent manner. The presence of CompB produced a parallel right-shift of the concentration-response curve to N/OFQ. The Schild plot analysis yielded a pA(2) value of 8.37. At concentrations up to 1 microM, CompB affected neither the membrane current per se nor the inwardly rectifying K(+) current activated by [D-Ala(2), N-Me-Phe(4),Gly-ol(5)]-enkephalin or baclofen, a mu-opioid and GABA(B) receptor agonist, respectively. It appears that CompB, at nanomolar concentrations, is a pure, selective and competitive antagonist of postsynaptic NOP receptors that mediate inwardly rectifying K(+) channel activation in ventrolateral PAG neurons.
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PMID:CompB (J-113397), selectively and competitively antagonizes nociceptin activation of inwardly rectifying K(+) channels in rat periaqueductal gray slices. 1206 9

The recently discovered endogenous peptide orphanin FQ/nociceptin (OFQ/N) activates the opioid receptor-like 1 (ORL1) receptor and produces diverse effects on pain perception. In addition to producing spinal analgesia, OFQ/N also exhibits an 'anti-opioid activity' against functional (supraspinal analgesia) and behavioral (conditioned place preference and withdrawal) properties of morphine. One manifestation of the behavioral changes resulting from chronic use of morphine is the upregulation of tyrosine hydroxylase (TH, the rate-limiting enzyme in catecholamine biosynthesis), which contributes to the dramatic increases in catecholamine release in the target regions of the locus coeruleus (LC) and the ventral tegmental area (VTA). The present study sought to determine the molecular mechanism(s) by which OFQ/N modulates the chronic actions of morphine by utilizing human neuroblastoma cell lines [BE(2)-C and SH-SY5Y] that endogenously express TH, and mu and ORL1 receptors. Activation of mu or ORL1 receptors in these cells in turn activates extracellular signal-regulated protein kinases (ERKs), ERK1 and ERK2. Chronic activation of mu, but not ORL1, receptors upregulated TH levels in these cells as previously reported in rat brain. Morphine-induced TH upregulation was blocked upon inclusion of a MEK-1 (mitogen-activated protein kinase kinase-1) inhibitor (PD98059), confirming the role for ERKs in this adaptive response to morphine. Inclusion of OFQ/N during chronic morphine exposure also blocked morphine-induced TH upregulation. Furthermore, chronic OFQ/N exposure increased levels of the TH gene repressor, Oct-2, irrespective of the presence or absence of morphine. This report suggests a potential role for Oct-2 in mediating the anti-opioid actions of OFQ/N against the behavioral manifestations resulting from chronic use of morphine.
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PMID:Orphanin FQ/nociceptin blocks chronic morphine-induced tyrosine hydroxylase upregulation. 1239 6

The opioid receptor-like 1 receptor is a novel member of the opioid receptor family and its endogenous peptide ligand has been termed nociceptin and orphanin FQ. Activation of the opioid receptor-like 1 receptor by nociceptin/orphanin FQ in vivo produces hyperalgesia when this peptide is given supraspinally but analgesia at the spinal level. Nociceptin/orphanin FQ also reverses stress-induced analgesia, suggesting that the peptide has anti-opioid properties. Nociceptin/orphanin FQ knockout mice show alterations in pain sensitivity and stress responses and display increased morphine dependence, suggesting an interaction of the nociceptin/orphanin FQ system with classical opioid receptor function. To determine if the behavioural phenotype of nociceptin/orphanin FQ knockout mice reflects changes in either opioid receptor-like 1 or classical opioid receptor expression, we have carried out quantitative autoradiography of the opioid receptor-like 1, mu-, delta- and kappa-opioid receptors in the brains of these animals. Receptor density was measured on coronal sections from wild-type, heterozygous and homozygous mice using [(3)H]nociceptin, [(3)H][D-Ala(2)-N-methyl-Phe(4)-Gly(5) ol] enkephalin, [(3)H]deltorphin-I, or [(3)H](-)-N-methyl-N-[7-(1-pyrrodinyl)-1-oxospiro[4,5]dec-8-yl]-4-benzofuranacetamide to label opioid receptor-like 1, mu-, delta- and kappa-receptors, respectively. A region-specific up-regulation of the opioid receptor-like 1 receptor (up to 135%) was seen in brains from homozygous mice. Mu-Receptors also showed significant differences between genotypes whilst changes in delta- and kappa- receptors were minor. In conclusion the region-specific up-regulation of the opioid receptor-like 1 receptor indicates a tonic role for nociceptin/orphanin FQ in some brain structures and may suggest the peptide regulates the receptor expression in these regions. The changes in the opioid receptor-like 1 receptor may relate to the anxiogenic phenotype of these animals but the observed change in mu-receptors does not correlate with altered morphine responses.
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PMID:Nociceptin/orphanin FQ knockout mice display up-regulation of the opioid receptor-like 1 receptor and alterations in opioid receptor expression in the brain. 1260 2

A peptide termed nociceptin/orphanin FQ (N/OFQ) was recently identified as an endogenous agonist for the opioid receptor-like receptor currently specified as NOP receptor. Despite many structural homologies to the opioid system, the NOP receptor shows low-affinity binding to selective opioid agonists or antagonists. Vice versa, N/OFQ selectively activates the NOP receptor but not any opioid receptor subtype. This novel receptor/ligand system is widely expressed in the brain. At the cellular level, the actions of N/OFQ resemble those elicited by opioid peptides. The NOP receptor is coupled to G-proteins, whose activation results in inhibition of adenylate cyclase, modulation of calcium and potassium conductances, and regulation of transmitter systems. At the behavioral level, systemic application of N/OFQ elicits a unique range of responses, including a wide range of effects on pain processing such as hyperalgesia, analgesia, and allodynia, as well as anxiolytic actions, modulation of opioid-mediated processes, and influences on learning and memory.
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PMID:Nociceptin/orphanin FQ: actions within the brain. 1270 19

The neuropeptide nociceptin, also called orphanin FQ (N/OFQ), is the endogenous agonist of the N/OFQ peptide receptor (NOP receptor). Both N/OFQ and the NOP receptor share a high degree of homology with classical opioid peptides and opioid receptors, respectively, and use similar signal transduction pathways as classical opioids. The NOP receptor has thus been regarded as the fourth member of the opioid receptor family. Despite this close relationship, 7 years of research have demonstrated that the N/OFQ system has a distinct pharmacological profile and serves different physiological functions. In particular, its role in the control of pain and analgesia at different levels of integration appears quite different from that of classical opioids. The recent development of specific antagonists at the NOP receptor and of NOP receptor or N/OFQ precursor knock-out mice have generated new insights into the role of N/OFQ in pain processing and help to evaluate the N/OFQ-NOP system as a potential target for new analgesic drugs.
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PMID:Nociceptin/orphanin FQ and its receptor--potential targets for pain therapy? 1272 34

Nociceptin/orphanin FQ (noc/oFQ) is the first novel bioactive substance to have been discovered by the implementation of a functional genomics/reverse pharmacology approach. The neuropeptide was indeed identified in brain extracts as the natural ligand of a previously cloned orphan G protein-coupled receptor, the opioid receptor-like 1 (ORL1) receptor. Since its discovery in 1995, noc/oFQ has been the subject of intensive study to establish its role in normal brain function and its possible involvement in neurophysiopathology. Although the neuropeptide, an inhibitor of neuronal activity, has been found to have a wide spectrum of pharmacological effects in vivo, none has been as intensively investigated as its action on nociception and nociceptive processing. There is now substantial evidence that noc/oFQ has a modulatory role in nociception. However, dependent on the dose and site of injection, and possibly the animal's genetic background and even psychological status, the peptide has been variously reported to cause allodynia, hyperalgesia, analgesia, and even pain, in rodents. Overall, noc/oFQ tends to facilitate pain when administered supraspinally, and to inhibit it when administered spinally. These opposing effects beg the obvious, yet still unanswered, question as to what would be the net effect on nociception of an ORL1 receptor ligand, agonist or antagonist, able to target supraspinal and spinal sites simultaneously. Owing to the research effort of several drug companies, such ligands, i.e. nonpeptidic, brain-penetrating agonists and antagonists, have recently been produced whose systematic screening in animal models of acute and inflammatory pain may help validate the ORL1 receptor as the target for novel, non-opioid analgesics.
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PMID:Utilizing functional genomics to identify new pain treatments : the example of nociceptin. 1274 29


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