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

We have identified a putative opioid receptor from mouse brain (KOR-3), belonging to the G protein-coupled receptor family, that is distinct from the previously cloned mu, delta, and kappa 1 receptors. Assignment of the clone to the opioid receptor family derives from both structural and functional studies. Its predicted amino acid sequence is highly homologous to that of the other opioid receptors, particularly in many of the transmembrane regions, where long stretches are identical to mu, delta, and kappa 1 receptors. Both cyclazocine and nalorphine inhibit cAMP accumulation in COS-7 cells stably expressing the clone. Northern analysis shows that the mRNA is present in brain but not in a number of other organs. Southern analysis suggests a single gene encoding the receptor. A highly selective monoclonal antibody directed against the native kappa 3 receptor recognizes, in Western analysis, the clone expressed in COS-7 cells. The in vitro translation product is also labeled by the antibody. Additional clones reveal the presence of several introns, including one in the second extracellular loop and another in the first transmembrane region. Antisense studies with an oligodeoxynucleotide directed against a region of the second extracellular loop reveal a selective blockade of kappa 3 analgesia in vivo that is not observed with a mismatch oligodeoxynucleotide based upon the antisense sequence. The mu, delta, and kappa 1 analgesia is unaffected by this antisense treatment. Antisense mapping of the clone downstream from the splice site in the first transmembrane region reveals that six different antisense oligodeoxynucleotides all block kappa 3 analgesia. In contrast, only one of an additional six different antisense oligodeoxynucleotides directed at regions upstream from this splice site is effective. This strong demarcation between the two regions raises the possibility of splice variants of the receptor. An additional clone reveals an insert in the 3' untranslated region. In conclusion, the antibody and antisense studies strongly associate KOR-3 with the kappa 3-opioid receptor, although it is not clear whether it is the kappa 3 receptor itself or a splice variant.
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PMID:Cloning and functional characterization through antisense mapping of a kappa 3-related opioid receptor. 760 58

Previous work reveals that orphanin FQ/nociceptin (OFQ/N) administered supraspinally produces an initial hyperalgesic response followed by analgesia. Spinally, OFQ/N elicits a rapidly appearing, naltrexone-reversible, dose-dependent analgesia in the tailflick assay without any indication of hyperalgesia. Two OFQ/N fragments, OFQ/N (1-7) and OFQ/N (1-11), are active, but far weaker. Blockade of sigma receptors with haloperidol enhances the analgesic potency of spinal OFQ/N, OFQ/N (1-7) and OFQ/N (1-11), but not as dramatically as supraspinal OFQ. Antisense probes targeting the second and third coding exons, but not the first exon, of the cloned mouse OFQ/N receptor (KOR-3) partially block OFQ/N analgesia.
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PMID:Spinal analgesic activity of orphanin FQ/nociceptin and its fragments. 908 86

The cloning of a fourth member of the opioid receptor family has led to the discovery of a new neuropeptide termed orphanin FQ or nociceptin (OFQ/N). Studies in CD-1 mice confirm the ability of OFQ/N to rapidly induce hyperalgesia within 15 min which is insensitive to opioid antagonists. This is followed in the next 30 min by loss of hyperalgesia and the appearance of analgesia in the tailflick assay which is readily reversed by opioid antagonists. However, the very poor affinity of OFQ/N for all the traditional opioid receptors and the insensitivity of OFQ/N analgesia to antisense oligodeoxynucleotides active against MOR-1, DOR-1 or KOR-1 sequences that selectively block mu, delta or kappa1 analgesia, respectively, make it unlikely that OFQ/N analgesia is mediated through typical opioid receptors. Blockade of the antiopioid sigma system by haloperidol enhances the analgesic potency of OFQ/N of more than 100-fold. This effect is pronounced in BALB-C and Swiss-Webster mice. Although OFQ/N alone has little analgesic activity in these mice, the blockade of sigma systems with haloperidol uncovers a robust analgesic response in both strains. Two shorter OFQ/N fragments, OFQ/N(1-7) and OFQ/N(1-11), also are analgesic in CD-1 mice and their actions are reversed by the opioid antagonist diprenorphine despite very poor affinities of both peptides against [125I]OFQ/N binding and all the opioid receptors. In antisense studies, a probe targeting the first coding exon of KOR-3 eliminates OFQ/N hyperalgesia, but not OFQ/N analgesia. Conversely, antisense probes based on the second and third coding exons are inactive against OFQ/N hyperalgesia but readily reverse kappa3 opioid analgesia. These results suggest that OFQ/N elicits both analgesia and hyperalgesia through pharmacologically distinct receptors that do not correspond to traditional opioid receptors.
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PMID:Pharmacological characterization of orphanin FQ/nociceptin and its fragments. 926 52

Homology cloning and, more recently, the sequencing of whole genomes, have identified many open reading frames encoding proteins of unknown function, in particular putative G protein-coupled membrane receptors. Identification of orphan receptors in this way has marked the advent of 'reverse pharmacology' to identify the corresponding physiological ligands. This approach has led to the discovery of the ORL1 (Opioid Receptor-Like 1) receptor, and of its natural ligand, nociceptin/orphanin FQ (noc/oFQ), the basic components of a new peptide-based signalling pathway in the nervous system. Based on genetic criteria, the ORL1 and opioid receptors belong to the same family, as do noc/oFQ and opioid peptides. The marked structural analogy between the ORLI and opioid receptors, especially the kappa-opioid receptor, and the noc/oFQ and opioid peptides, particularly dynorphin A, is not reflected anatomically since noc/oFQ and opioid peptides appear to be located in separate neuronal circuits. Noc/oFQ triggers the same G protein-mediated signalling pathways as do opioids, however, to produce pharmacological effects that sometimes differ from, and even oppose, those of opioids. Noc/oFQ stimulates an outward K+ current and/or inhibits voltage-gated Ca2+ channels, thereby reducing synaptic efficacy, i.e. neuronal activity. In the rat, noc/oFQ is endowed with supraspinal pronociceptive/anti-opioid properties (it suppresses opioid-mediated analgesia), while convergent electrophysiological and behavioural data indicate that the peptide is a spinal analgesic. Noc/oFQ has not yet been found to precipitate withdrawal in morphine-tolerant rats. Nor does it elicit motivational effects, suggesting it lacks abuse liability. Also, by acting supraspinally, noc/oFQ impairs motor performance, suppresses spatial learning, induces feeding, and regulates basal and stress-induced release of pituitary hormones. Noc/oFQ is also active when administered intravenously, exhibiting potent smooth muscle relaxant, diuretic, and antinatriuretic properties. Last but not least, noc/oFQ appears to regulate stimulated immune function, and to be involved in neuronal differentiation. The discovery of noc/oFQ, a neuropeptide with multiple functions, will certainly improve our knowledge of brain physiology, and may find therapeutic applications, for example in the management of pain or hyponatremic and water-retaining diseases. However, given the wide distribution of noc/oFQ and its receptor, the pharmacological profile of noc/oFQ is likely to be incomplete, and other as yet unknown functions of the peptide remain to be discovered. Most helpful in this respect will be the identification of new ligands of the ORL1 receptor, particularly antagonists. If research on noc/oFQ carries on unabated at the present pace, potentially clinically interesting new compounds could become available in the not too distant future.
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PMID:Nociceptin/orphanin FQ and the opioid receptor-like ORL1 receptor. 952 1

Opioids form the major class of strong analgesics. Endogenous opioids and their receptors play important roles in central nervous system function. Thus, the discovery of a new opioid peptide, nociceptin or orphanin FQ, and its receptor, opioid receptor-like 1 (ORL-1) has caused considerable interest since this transmitter system appears to exhibit a number of key differences to the other opioids. Analgesia can be produced at spinal sites but there is compelling evidence that the peptide may also have 'anti-opioid' actions in the brain. Effects on auditory processing, pains from nerve injury coupled with an apparent lack of motivational effects have important implications for novel therapy. This review surveys the recent functional studies on this novel peptide.
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PMID:Nociceptin/orphanin FQ. A new opioid, a new analgesic? 976 Jan 2

The orphanin FQ/nociceptin (OFQ/N) derivative peptide, [Phe1psi(CH2-NH)Gly2] nociceptin-(1-13)-NH2 (Phe(psi)), has been claimed to be both an antagonist and an agonist of the orphan opioid receptor (ORL1) in different in vitro assays. We now report the dose-dependent inhibition of morphine analgesia by Phe(psi) in mice, an effect parallel to that of OFQ/N. Further, the anti-opioid actions of OFQ/N are not blocked by Phe(psi). Thus, Phe(psi) acts as an ORL1 receptor agonist, not an antagonist, in vivo.
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PMID:[Phe1psi(CH2-NH)Gly2]nociceptin-(1-13)-NH2 acts as an agonist of the orphanin FQ/nociceptin receptor in vivo. 978 79

Opiate drugs such as morphine stimulate food intake in rats. The morphine metabolite, morphine-6beta-glucuronide (M6G), is more active than morphine in analgesic assays, and appears to act through distinct receptors. Thus, although morphine analgesia is decreased by antisense oligodeoxynucleotides (AS ODNs) targeting exons 1 and 4 of the MOR-1 clone, M6G analgesia is reduced by probes targeting exons 2 and 3 of the MOR-1 clone. Our study examined whether central administration of M6G increased food intake in rats, and characterized this response using either selective mu, kappa1, delta1 and delta2 antagonists, or antisense directed against the various cloned opioid receptors. Central M6G (10-1000 ng) significantly and dose-dependently increased intake after 4 hr. Whereas mu antagonism with betaFNA significantly and dose-dependently reduced M6G-induced hyperphagia, equimolar doses of delta1, delta2, and kappa1 antagonists were ineffective. AS ODNs directed against either exons 2 or 3 of the MOR-1 clone blocked M6G-induced hyperphagia, whereas either AS ODNs directed against exons 1 or 4, or a MS ODN directed against exon 2 were ineffective. In contrast, an AS ODN probe directed against exon 1, but not exon 2, of the MOR-1 clone reduced morphine-induced hyperphagia, an effect identical to DAMGO-induced hyperphagia. Whereas M6G-induced hyperphagia was insensitive to antisense probes directed against the DOR-1, KOR-1 and KOR-3/ORL1 clones, these probes respectively reduced hyperphagia induced by deltorphin II, U50488H and nociceptin. Although pharmacological data indicate that M6G-induced hyperphagia acts through mu receptors, antisense data imply that the hyperphagic actions of M6G are mediated by a receptor distinct from traditional mu agonists, either as an alternative splice variant of the MOR-1 clone or a distinct gene.
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PMID:Morphine-6beta-glucuronide-induced hyperphagia: characterization of opioid action by selective antagonists and antisense mapping in rats. 980 78

Orphanin FQ/nociceptin (OFQ/N) is a recently identified neuropeptide with high affinity for the orphan opioid receptor. OFQ/N blocked morphine analgesia in mice in a dose-dependent manner, as well as the analgesic actions of [D-Pen2, D-Pen5]enkephalin (DPDPE), morphine-6 beta-glucuronide, trans-3,4-dichloro-N-[2-(1-pyrrolindinyl)-cyclohexyl]-benzeneac eta mide, methane sulfonate hydrate (U50,488H) and naloxone benzoylhydrazone. These actions are anti-analgesic, because OFQ/N also blocked clonidine analgesia and OFQ/N was inactive against the inhibition of gastrointestinal transit by morphine. Although OFQ/N was quite potent in these paradigms, two truncated forms, OFQ/N(1-11) and OFQ/N(1-7), were inactive. An antisense oligodeoxynucleotide targeting the first coding exon of KOR-3, the mouse homolog of the orphan opioid receptor, effectively prevented the anti-opioid actions of OFQ/N, confirming the importance of the orphan opioid receptor in this action.
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PMID:Functional blockade of opioid analgesia by orphanin FQ/nociceptin. 1007 48

Orphanin FQ/Nociceptin (OFQ/N) administered peripherally was an effective analgesic in the tailflick test in mice (ED50 16.3 microg). It had a peak effect at 5 min and lasted up to 30 min. The kappa3 analgesic naloxone benzoylhydrazone was also active peripherally (ED50 3.8 microg). The analgesic actions of both agents were blocked by naloxone. Neither OFQ/N(1-11) nor OFQ/N(1-7) had appreciable peripheral activity. Antisense mapping both compounds against the murine orphan opioid receptor (KOR-3) confirmed the importance of this clone in their actions. Antisense probes targeting the second and third coding exons significantly lowered the analgesic effects of both compounds. However, the antisense targeting the first coding exon blocked only the actions of OFQ/N and not kappa3 analgesia.
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PMID:Peripheral orphanin FQ/nociceptin analgesia in the mouse. 1037 27

Orphanin FQ (also known as nociceptin) is a 17-amino-acid peptide which acts as a potent endogenous agonist of the orphan opioid receptor-like (ORL1) receptor. Endomorphin-1, a 4-amino-acid peptide discovered recently, is a potent and selective endogenous agonist for the mu-opiate receptor. In the present study, the effect of OFQ or/and endomorphin-1 on the response to noxious thermal stimuli was observed using the tail-flick test in rats. Intracerebroventricular (i.c.v.) administration of OFQ (1, 5 microg) could shorten tail-flick latency; In contrast, intrathecal (i.t.) administration of OFQ (1, 2 or 10 microg) could increase the latency; i.c.v. (1, 2, 5 microg) or i.t. (0.2, 2, 5 microg) administration of endomorphin-1 dose-dependently increased the latency, indicating an analgesic effect. Furthermore, OFQ (0.1-5 microg) when intraventricularly injected together with endomorphin-1 (5 microg), could dose-dependently reverse the analgesia induced by the latter. On the contrary, OFQ (1 microg) intrathecally injected together with endomorphin-1 (0.2 microg) could further increase the tail-flick latency. The results showed that OFQ at the supraspinal level produces hyperalgesia and is antagonistic to endomorphin-1, while at the spinal level it produces analgesia and is synergic with endomorphin-1. Different interaction mechanism between OFQ and endomorphin-1 in the brain and the spinal cord is thus suggested.
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PMID:Effects of orphanin FQ on endomorphin-1 induced analgesia. 1041 79


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