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)

Orphanin FQ (OFQ), the endogenous ligand for the orphan opioid receptor, LC132, was recently isolated and characterized. The anti-opioid role of OFQ in supraspinal pain modulation was demonstrated by our previous observations that intracerebroventricular (i.c.v.) OFQ administration dose-dependently reverses systemic morphine antinociception and opioid-mediated stress-induced antinociception. The present study was designed to evaluate whether OFQ also modulates the antinociceptive actions of morphine in the spinal cord. Immediately after assessment of baseline nociceptive sensitivity on the 49 degrees C tail-withdrawal assay, mice of both sexes were given i.c.v. or intrathecal (i.t.) cocktails of morphine (0, 1, 10 or 50 micrograms [0-135 nmol]) and OFQ (0 or 10 nmol), and re-tested 15, 30 and 60 min later. OFQ alone did not affect nociceptive sensitivity when administered by either route. Following i.c.v. administration, the antinociception produced by 10 micrograms morphine was completely reversed by 10 nmol OFQ; antinociception induced by 50 micrograms morphine was significantly antagonized. In contrast, OFQ was completely ineffective against antinociception induced by i.t. morphine. These findings indicate that the anti-opioid actions of OFQ are restricted to supraspinal central nervous system sites.
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PMID:Orphanin FQ acts as a supraspinal, but not a spinal, anti-opioid peptide. 893 Sep 72

1. The present study was designed to investigate further the effects of the newly discovered orphanin FQ (OFQ)-the endogenous ligand for the orphan opioid receptor (called, e.g., ORL, and LC132)-on pain modulation in the rat. We used the tail-flick assay as a nociceptive index. 2. When injected into a cerebral ventricle, OFQ (4 fmol-10 nmol) has no effect on basal tail-flick latency by itself at any dose, but dose-dependently antagonizes systemic morphine analgesia (400 fmol 50 nmol). 3. Injected intrathecally, OFQ (3 and 10 nmol) displayed an analgesic effect without producing motor dysfunction, and potentiated morphine analgesia (1 and 10 nmol). 4. The anti-opioid effect of OFQ in rat brain and the high level of expression of LC132/ORL, receptor in the locus coeruleus indicated a possible role of OFQ in the precipitation of opiate withdrawal symptoms. However, no such precipitation was observed by OFQ in morphine-dependent rats.
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PMID:Bidirectional modulatory effect of orphanin FQ on morphine-induced analgesia: antagonism in brain and potentiation in spinal cord of the rat. 905 7

Taking advantage of the functional coupling of the nociceptin/orphanin FQ receptor with the G-protein-activated inwardly rectifying K+ (GIRK) channel, we investigated the effects of various sigma ligands on the nociceptin/orphanin FQ receptor in Xenopus oocytes co-injected with the cloned nociceptin/orphanin FQ receptor and GIRK1 mRNAs. Carbetapentane and rimcazole, which induced no current response at 100 microM, reversibly suppressed the inward K+ current responses induced by nociceptin in a concentration-dependent manner, and the IC50 values (microM) for these compounds were 9.0 and 12.6, respectively. (+/-)-N-allylnormetazocine. (+)-cyclazocine, (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and 1,3-di-(2-tolyl)guanidine, at 100 microM, had no effect on the receptor. These results suggest that carbetapentane and rimcazole act as antagonists at the nociceptin/orphanin FQ receptor and may be involved in pain regulation.
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PMID:Effects of sigma ligands on the nociceptin/orphanin FQ receptor co-expressed with the G-protein-activated K+ channel in Xenopus oocytes. 913 6

1. Intrathecal (i.t.) administration of nociceptin and high doses of morphine induced allodynia in response to innocuous tactile stimuli, and i.t. nociceptin evoked hyperalgesia in response to noxious thermal stimuli in conscious mice. Here we have characterized the nociceptin-induced allodynia and compared it with the morphine-induced allodynia and the nociceptin-evoked hyperalgesia. 2. Nociceptin-induced allodynia was evoked by the first stimulus 5 min after i.t. injection, reached a maximum at 10 min, and continued for a 50 min experimental period. Dose-dependency of the allodynia showed a bell-shaped pattern from 50 pg to 5 ng kg-1, and the maximum effect was observed at 2.5 ng kg-1. 3. Morphine-induced allodynia reached the maximum effect at 15 min and declined progressively until cessation by 40-50 min. The dose-response curve showed a bell-shaped pattern, similar to that induced by nociceptin, with a maximum effect at 0.5 mg kg-1, five orders of magnitude higher than that of nociceptin. 4. The allodynia evoked by nociceptin and morphine were dose-dependently blocked by glycine, D(-)-2-amino-5-phosphonovaleric acid (D-AP5, an N-methyl-D-aspartate (NMDA) receptor antagonist), gamma-D-glutamylaminomethyl sulphonic acid (GAMS, a non-NMDA receptor antagonist) and methylene blue (a soluble guanylate cyclase inhibitor), but were not affected by muscimol (a gamma-aminobutyric acidA (GABAA) receptor agonist) and baclofen (a GABAB receptor agonist). 5. Morphine did not inhibit forskolin-stimulated cyclicAMP formation in cultured cells expressing the nociceptin receptor. 6. Nociceptin-induced hyperalgesia was evoked 10-15 min after i.t. injection. Nociceptin produced a monophasic hyperalgesic action over a wide range of doses from 5 fg to 50 ng kg-1. The nociceptin-induced hyperalgesia was blocked by glycine only among the agents examined. 7. None of the pain responses evoked by nociceptin and morphine were blocked by naloxone. 8. These results demonstrate that, whereas the mechanisms of the nociceptin-induced allodynia and hyperalgesia are evidently distinct, they involve a common neurochemical event beginning with the disinhibition of the inhibitory glycinergic response. Morphine may induce allodynia through a pathway common to nociceptin, but the nociceptin receptor does not mediate the action of high doses of morphine.
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PMID:Characterization of nociceptin hyperalgesia and allodynia in conscious mice. 917 80

Prolonged tissue damage or injury often leads to chronic pain states such that noxious stimuli evoke hyperalgesia and innocuous tactile stimuli evoke pain (allodynia). The neuropeptide nociceptin, also known as orphanin FQ, is an endogenous ligand for the orphan opioid-like receptor which induces both hyperalgesia and allodynia when administered by injection through the theca of the spinal cord into the subarachnoid space (that is, intrathecally). Here we show that the nociceptin precursor contains another biologically active peptide which we call nocistatin. Nocistatin blocks nociceptin-induced allodynia and hyperalgesia, and attenuates pain evoked by prostaglandin E2. It is the carboxy-terminal hexapeptide of nocistatin (Glu-Gln-Lys-Gln-Leu-Gln), which is conserved in bovine, human and murine species, that possesses allodynia-blocking activity. We have also isolated endogenous nocistatin from bovine brain. Furthermore, intrathecal pretreatment with anti-nocistatin antibody decreases the threshold for nociceptin-induced allodynia. Although nocistatin does not bind to the nociceptin receptor, it binds to the membrane of mouse brain and of spinal cord with high affinity. Our results show that nocistatin is a new biologically active peptide produced from the same precursor as nociceptin and indicate that these two peptides may play opposite roles in pain transmission.
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PMID:Nocistatin, a peptide that blocks nociceptin action in pain transmission. 952 23

We examined the effects of intrathecal nociceptin, the endogenous ligand for the orphan opioid receptor-like receptor, on abnormal pain-related behaviors in rats after carrageenan-induced inflammation and photochemically-induced peripheral nerve or spinal cord ischemic injury. Intrathecal nociceptin dose-dependently alleviated mechanical and cold allodynia-like behavior in the two models of neuropathic pain. The heat hyperalgesia associated with peripheral inflammation was also significantly reduced, although the efficacy of the antihyperalgesic effect of nociceptin in the inflammation model was decreased. Intrathecal nociceptin also induced significant antinociception on the tail-flick test in all three groups of rats. However, the antinociceptive effect of nociceptin was significantly reduced in rats with peripheral nerve injury. These results indicated that spinally administered nociceptin has anti-allodynic and anti-hyperalgesic effects in animal models of tonic or chronic pain of different origins. Peripheral inflammation and nerve injury may induce spinal plasticity which leads to altered potency and efficacy of nociceptin.
Pain 1998 Jun
PMID:Anti-hyperalgesic and anti-allodynic effects of intrathecal nociceptin/orphanin FQ in rats after spinal cord injury, peripheral nerve injury and inflammation. 971 57

We have measured plasma and cerebrospinal fluid (CSF) concentrations of nociceptin, the endogenous agonist of the orphan opioid receptor-like receptor (ORL-1). We studied two groups of ten patients presenting for elective Caesarean section (Group E) or in established labour and requiring combined spinal epidural anaesthesia for pain relief (Group L). Nociceptin was identified in all CSF samples with mean +/- SD concentrations of 52.49 +/- 34.25 and 63.39 +/- 33.26 pg/ml in groups E and L, respectively. Nociceptin was identified in 16/20 plasma samples with mean +/- SD concentrations of 7.59 +/- 21.58 and 13 73 +/- 23.79 pg/ml in groups E and L, respectively. CSF concentrations were significantly higher than plasma concentrations and there were no differences between groups E and L. These data report the first measurements of CSF nociceptin in man and show no association with the acute pain of labour.
Pain 1998 Oct
PMID:Identification of nociceptin in human cerebrospinal fluid: comparison of levels in pain and non-pain states. 982 13

Nociceptin/orphanin FQ (nociceptin/OFQ), a newly discovered heptadecapeptide has been regarded as an endogenous ligand for orphan opioid receptor. The present study was designed to investigate the effect of nociceptin/OFQ on pain response and opioid analgesia in the rat formalin test. The results showed that intracerebroventricular injection of 1 microg nociceptin/OFQ enhanced the pain response, and 0.1 or 0.5 microg nociceptin/OFQ had no effect on formalin-induced pain. When 0.1 or 1 microg nociceptin/OFQ were used together with mu-, delta-, or kappa-opioid receptor agonists, endomorphin-1, DSLET or U50488H, respectively, it attenuated mu- and kappa- but not delta-receptor mediated analgesia. On the other hand, intrathecal injection of nociceptin/OFQ (0.1, 1 and 5 microg) reduced the pain response in the formalin test. In conclusion, nociceptin/OFQ potentiated formalin-induced pain response and antagonized opioid analgesia in the rat brain but inhibited pain response in the spinal cord.
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PMID:Distinct effect of intracerebroventricular and intrathecal injections of nociceptin/orphanin FQ in the rat formalin test. 1010 Sep 30

Nociceptin (orphanin FQ), the newly discovered endogenous ligand for the novel opioid receptor-like 1 receptor, has been initially found to participate in pain modulation. In this study, centrally mediated cardiovascular actions of this peptide were investigated in the alpha-chloralose/urethane-anesthetized rats. We found that bilateral injection of nociceptin (10 nmol) into the rostral ventrolateral medulla (RVLM), wherein injection of excitatory amino acid dl-homocysteic acid (3 nmol) induced typical pressor responses, significantly reduced arterial blood pressure and heart rate by -32% and -15%, respectively. Reduction of blood pressure and heart rate in response to intra-RVLM injection of nociceptin was dose-dependent with a threshold dose being 3 nmol. Pretreatment with the selective nociceptin receptor antagonist, [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2 (10 nmol), into the RVLM abolished the nociceptin-induced cardiovascular inhibition. In contrast, non-selective opioid receptor antagonist, naloxone (10 nmol), did not modify the hypotension and bradycardia induced by nociceptin, even though naloxone at the same dose prevented reduction of blood pressure and heart rate induced by intra-RVLM injection of methionine-enkephalin (3 nmol). Both [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2 and naloxone injection alone had no significant effect on baseline blood pressure and heart rate. These data suggest that the newly discovered opioid-like neuropeptide nociceptin in the CNS exert powerful influence on hemodynamic activity by affecting the RVLM neurons. This influence is inhibitory in nature, which may not be active in normal physiological conditions. Moreover, the cardiovascular effects of nociceptin were mediated by activation of specific nociceptin receptors rather than typical naloxone-sensitive opioid receptors.
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PMID:Inhibition of cardiovascular activity following microinjection of novel opioid-like neuropeptide nociceptin (orphanin FQ) into the rat rostral ventrolateral medulla. 1035 May 39

Nociceptin and nociceptin receptor, which show structural similarities to opioid peptides and opioid receptors, respectively, have been recently found to constitute a novel neuromodulatory system. In the central nervous system, however, the physiological role of modulation via the nociceptin receptor is still unclear. Here, we report the behavioral pharmacological characterization of mice lacking the nociceptin receptor. Nociceptin produced hyperalgesia and hypolocomotion, whereas the nociceptin receptor-knockout mice showed no significant abnormalities in nociceptive thresholds (tail-flick, hot-plate, electric, and acetic acid-induced writhing tests) and locomotion. In the learning and memory tests, nociceptin induced impairment of learning and memory in wild-type mice. Nociceptin receptor-knockout mice possessed greater learning ability and had better memory than wild-type mice. These results suggest that the nociceptin system plays a role in regulation of nociception or locomotion and seems to play negative roles in learning and memory. Next, we compared nociceptive responses induced by various opioids between the nociceptin receptor-knockout and wild-type mice. As previously reported, morphine (mu-opioid receptor agonist), U-50,488 H (kappa 1-opioid receptor agonist), and naloxone benzoylhydrazone (NalBzoH; kappa 3-opioid receptor agonist) induced antinociceptive effects in wild-type mice. Surprisingly, knockout mice lacked the antinociceptive effect induced by NalBzoH, but not by morphine and U-50,488H. Further, NalBzoH completely inhibited nociceptin-induced hyperalgesia and hypolocomotion in wild-type mice. Experiments on the cultured cells transfected with the nociceptin receptor cDNA showed that NalBzoH competed in [3H]-nociceptin binding and attenuated the nociceptin-induced inhibition of cyclic AMP accumulation induced by forskolin. These results clearly suggest that NalBzoH acts as a potent antagonist for the nociceptin receptor. Our studies suggest that the nociceptive system and/or learning and memory processes could be modulated by ligands to the nociceptin receptor, and further that the antagonists are worth testing for the alleviation of pain and memory disorders.
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PMID:[Behavioral pharmacological characterization of mice lacking the nociceptin receptor]. 1046 78


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