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)

A novel G protein-coupled receptor was cloned by PCR and homology screening. Its deduced amino acid sequence is 47% identical overall to the mu, delta and kappa opioid receptors and 64% identical in the putative transmembrane domains. When transiently expressed in COS-7 cells this receptor did not bind any of the typical mu, delta or kappa opioid receptor ligands with high affinity. In situ hybridization analysis revealed that LC132 mRNA is highly expressed in several rat brain areas, including the cerebral cortex, thalamus, subfornical organ, habenula, hypothalamus, central gray, dorsal raphe, locus coeruleus and the dorsal horn of the spinal cord. Based on this distribution and its high homology with the mu, delta and kappa opioid receptors, it is proposed that LC132 is a new member of the opioid receptor family that is involved in analgesia and the perception of pain.
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PMID:Molecular cloning and tissue distribution of a putative member of the rat opioid receptor gene family that is not a mu, delta or kappa opioid receptor type. 803 19

Kinins are proinflammatory peptides that dilate vessels, increase vascular permeability, contract smooth muscles, and provoke pain. The known mammalian kinin receptors are classified as two subtypes, i.e. the B1 receptor triggered by [des-Arg9]bradykinin and inhibited by [des-Arg9,Leu8]bradykinin, and the B2 receptor stimulated by bradykinin and antagonized by HOE140. Here we report the cloning of a non-mammalian kinin receptor gene amplified from genomic chicken DNA. The protein predicted from the open reading frame shows 31 and 49% sequence identity to the human B1 and B2 receptors, respectively, suggesting that it represents a G protein-coupled receptor of the kinin receptor family. The recombinantly expressed chicken receptor had IC50 values of 4.7 nM for the authentic ligand, ornithokinin ([Thr6,Leu8]bradykinin), 3.8 nM for HOE140, and >/=10 microM for bradykinin, [des-Arg9]bradykinin, and [des-Arg9,Leu8]bradykinin. Ornithokinin and HOE140 at nanomolar concentrations stimulated intracellular inositol phosphate accumulation and induced a significant transient rise in intracelluar free Ca2+, whereas bradykinin was ineffective even at 100 nM. Hence the principal B2 receptor antagonist HOE140 is a potent agonist of the chicken kinin receptor. This unique pharmacological profile classifies the ornithokinin receptor as a novel subtype among kinin receptors and will facilitate further molecular studies on ligand binding and receptor activation.
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PMID:Cloning and functional characterization of the ornithokinin receptor. Recognition of the major kinin receptor antagonist, HOE140, as a full agonist. 913 96

Calcitonin generelated peptide (CGRP) is a neuropeptide discovered by a molecular approach over 10 years ago. More recently, islet amyloid polypeptide or amylin, and adrenomedullin were isolated from human insulinoma and pheochromocytoma respectively, and revealed between 25 and 50% sequence homology with CGRP. This review discusses findings on the anatomical distributions of CGRP mRNA, CGRP-like immunoreactivity and receptors in the central nervous system, as well as the potential physiological roles for CGRP. The anatomical distribution and biological activities of amylin and adrenomedullin are also presented. Based upon the differential biological activity of various CGRP analogs, the CGRP receptors have been classified in two major classes, namely the CGRP1 and CGRP2 subtypes. A third subtype has also been proposed (e.g. in the nucleus accumbens) as it does not share the pharmacological properties of the other two classes. The anatomical distribution and the pharmacological characteristics of amylin binding sites in the rat brain are different from those reported for CGRP but share several similarities with the salmon calcitonin receptors. The receptors identified thus far for CGRP and related peptides belong to the G protein-coupled receptor superfamily. Indeed, modulation of adenylate cyclase activity following receptor activation has been reported for CGRP, amylin and adrenomedullin. Furthermore, the binding affinity of CGRP and related peptides is modulated by nucleotides such as GTP. The cloning of various calcitonin and most recently of CGRP1 and adrenomedullin receptors was reported and revealed structural similarities but also significant differences to other members of the G protein-coupled receptors. They may thus form a new subfamily. The cloning of the amylin receptor(s) as well as of the other putative CGRP receptor subtype(s) are still awaited. Finally, a broad variety of biological activities has been described for CGRP-like peptides. These include vasodilation, nociception, glucose uptake and the stimulation of glycolysis in skeletal muscles. These effects may thus suggest their potential role and therapeutic applications in migraine, subarachnoid haemorrhage, diabetes and pain-related mechanisms, among other disorders.
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PMID:Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. 935 97

We have studied the in vivo signaling mechanisms involved in nociceptin/orphanin FQ (Noci)-induced pain responses by using a flexor-reflex paradigm. Noci was 10,000 times more potent than substance P (SP) in eliciting flexor responses after intraplantar injection into the hind limb of mice, but the action of Noci seems to be mediated by SP. Mice pretreated with an NK1 tachykinin receptor antagonist or capsaicin, or mice with a targeted disruption of the tachykinin 1 gene no longer respond to Noci. The action of Noci appears to be mediated by the Noci receptor, a pertussis toxin-sensitive G protein-coupled receptor that stimulates inositol trisphosphate receptor and Ca2+ influx. These findings suggest that Noci indirectly stimulates nerve endings of nociceptive primary afferent neurons through a local SP release.
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PMID:Nociceptin/orphanin FQ-induced nociceptive responses through substance P release from peripheral nerve endings in mice. 972 10

The substance P receptor (SPR) is a G protein-coupled receptor (GPCR) that plays a key role in pain regulation. The SPR desensitizes in the continued presence of agonist, presumably via mechanisms that implicate G protein-coupled receptor kinases (GRKs) and beta-arrestins. The temporal relationship of these proposed biochemical events has never been established for any GPCR other than rhodopsin beyond the resolution provided by biochemical assays. We investigate the real-time activation and desensitization of the human SPR in live HEK293 cells using green fluorescent protein conjugates of protein kinase C, GRK2, and beta-arrestin 2. The translocation of protein kinase C betaII-green fluorescent protein to and from the plasma membrane in response to substance P indicates that the human SPR becomes activated within seconds of agonist exposure, and the response desensitizes within 30 s. This desensitization process coincides with a redistribution of GRK2 from the cytosol to the plasma membrane, followed by a robust redistribution of beta-arrestin 2 and a profound change in cell morphology that occurs after 1 min of SPR stimulation. These data establish a role for GRKs and beta-arrestins in homologous desensitization of the SPR and provide the first visual and temporal resolution of the sequence of events underlying homologous desensitization of a GPCR in living cells.
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PMID:Real-time visualization of the cellular redistribution of G protein-coupled receptor kinase 2 and beta-arrestin 2 during homologous desensitization of the substance P receptor. 1006 24

Opiate tolerance and dependence are major clinical and social problems. The anti-opiate neuropeptides FF and AF (NPFF and NPAF) have been implicated in pain modulation as well as in opioid tolerance and may play a critical role in this process, although their mechanism of action has remained unknown. Here we describe a cDNA encoding a novel neuropeptide Y-like human orphan G protein-coupled receptor (GPCR), referred to as HLWAR77 for which NPAF and NPFF have high affinity. Cells transiently or stably expressing HLWAR77 bind and respond in a concentration-dependent manner to NPAF and NPFF and are also weakly activated by FMRF-amide (Phe-Met-Arg-Phe-amide) and a variety of related peptides. The high affinity and potency of human NPFF and human NPAF for HLWAR77 strongly suggest that these are the cognate ligands for this receptor. Expression of HLWAR77 was demonstrated in brain regions associated with opiate activity, consistent with the pain-modulating activity of these peptides, whereas the expression in adipose tissue suggests other physiological and pathophysiological activities for FMRF-amide neuropeptides. The discovery that the anti-opiate neuropeptides are the endogenous ligands for HLWAR77 will aid in defining the physiological role(s) of these ligands and facilitate the identification of receptor agonists and antagonists.
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PMID:Receptor for the pain modulatory neuropeptides FF and AF is an orphan G protein-coupled receptor. 1085 Dec 42

The nociceptin receptor (Noci-R) is a G protein-coupled receptor present in neural tissues and its activation by nociceptin is involved in the processing of pain signals. Here, we report that Noci-R is present and functional on peripheral blood polymorphonuclear leukocytes (PMN). Human PMN express mRNA for Noci-R, its nucleotide sequence determined, and specific binding with [(125)I]-labeled nociceptin gave an apparent K(d) approximately 1.5 nM for this PMN opioid receptor. Nociceptin evoked PMN chemotaxis with maximal activity at 100 pM, without intracellular Ca(2+) mobilization. When injected in murine air pouches, nociceptin elicited leukocyte infiltration in a concentration-dependent fashion. Nociceptin-stimulated PMN infiltration was inhibited by treating mice with a synthetic analog of the aspirin-triggered lipid mediator 15-epi-lipoxin A(4). The present results identify nociceptin as a potent chemoattractant and provide a novel link between the neural and immune systems that are blocked by aspirin-triggered lipid mediators and may be relevant in neurogenic inflammation.
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PMID:Cutting edge: nociceptin stimulates neutrophil chemotaxis and recruitment: inhibition by aspirin-triggered-15-epi-lipoxin A4. 1123 2

G protein-coupled receptors (GPCRs) mediate our sense of vision, smell, taste, and pain. They are also involved in cell recognition and communication processes, and hence have emerged as a prominent superfamily for drug targets. Unfortunately, the atomic-level structure is available for only one GPCR (bovine rhodopsin), making it difficult to use structure-based methods to design drugs and mutation experiments. We have recently developed first principles methods (MembStruk and HierDock) for predicting structure of GPCRs, and for predicting the ligand binding sites and relative binding affinities. Comparing to the one case with structural data, bovine rhodopsin, we find good accuracy in both the structure of the protein and of the bound ligand. We report here the application of MembStruk and HierDock to beta1-adrenergic receptor, endothelial differential gene 6, mouse and rat I7 olfactory receptors, and human sweet receptor. We find that the predicted structure of beta1-adrenergic receptor leads to a binding site for epinephrine that agrees well with the mutation experiments. Similarly the predicted binding sites and affinities for endothelial differential gene 6, mouse and rat I7 olfactory receptors, and human sweet receptor are consistent with the available experimental data. These predicted structures and binding sites allow the design of mutation experiments to validate and improve the structure and function prediction methods. As these structures are validated they can be used as targets for the design of new receptor-selective antagonists or agonists for GPCRs.
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PMID:Prediction of structure and function of G protein-coupled receptors. 1235 77

Intrathecal [D-Pen2,D-Pen5]-enkephalin (DPDPE; a delta-opioid agonist) has a profound antinociceptive effect in neuropathic pain. Spinal nitric oxide (NO) has been implicated in the analgesic effect of several G protein-coupled receptor agonists. Little, however, is known about the role of spinal NO in the inhibitory effect of DPDPE on spinal dorsal horn neurons. In the present study, we determined the role of NO in the inhibitory effect of DPDPE on ascending dorsal horn neurons in normal rats and in a rat model of diabetic neuropathic pain. Single-unit activity of ascending dorsal horn neurons was recorded in anesthetized rats. The responses of dorsal horn neurons to graded mechanical stimuli and von Frey filaments were determined before and after local spinal application of 0.1 to 5 microM DPDPE. The influence of an NO synthase inhibitor, 1-(2-trifluoromethylphenyl) imidazole (TRIM; 30 microM), on the effect of DPDPE was then studied in separate groups of dorsal horn neurons in normal and diabetic rats. DPDPE inhibited the response of dorsal horn neurons in both normal and diabetic rats in a concentration-dependent fashion. The inhibitory effect of 1 microM DPDPE was abolished by 1 microM naltrindole, a delta-opioid antagonist. Furthermore, the inhibitory effect of DPDPE on the evoked response of dorsal horn neurons was largely eliminated by TRIM in normal and diabetic rats. These data suggest that DPDPE has a profound inhibitory effect on dorsal horn neurons in normal and diabetic rats. Spinal endogenous NO is essential for the inhibitory effect of DPDPE on ascending dorsal horn neurons in both normal and diabetic rats.
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PMID:Role of spinal nitric oxide in the inhibitory effect of [D-Pen2, D-Pen5]-enkephalin on ascending dorsal horn neurons in normal and diabetic rats. 1243 23

The analgesia produced by inhibitory G protein-coupled receptor agonists involves coordinated postsynaptic inhibition via G protein-coupled inwardly rectifying potassium channels (GIRKs) and presynaptic inhibition of neurotransmitter release through regulation of voltage-gated Ca(2+) channels. Here, we used mice lacking the GIRK2 channel subunit to assess the relative contribution of these two effector systems to nociceptive processing in male and female mice. Compared with female WT mice, male WT mice exhibited higher pain thresholds and enhanced opioid (morphine) and alpha(2)-adrenergic (clonidine) receptor-induced antinociception in a spinal reflex test. The GIRK2-null mutation reduced the "pain" threshold in male but not in female mice, effectively eliminating the sex differences in pain threshold. In addition, deletion of GIRK2 channels in mutant mice largely eliminated clonidine antinociception and significantly decreased morphine antinociception. Furthermore, the more pronounced morphine and clonidine-induced antinociception in male mice disappeared in the GIRK2 mutants. Based on the almost complete loss of clonidine-induced antinociception in the mutant mice, we conclude that it is primarily mediated by postsynaptic alpha(2)-adrenergic receptors. In contrast, the significant residual morphine effect in the mutant mice points to the presynaptic mu opioid receptor as a major contributor to its analgesic action. Finally, our results suggest that the reduced pain responsiveness of male compared with female mice results in part from GIRK2-coupled postsynaptic receptors that are activated by endogenous antinociceptive systems.
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PMID:Contribution of GIRK2-mediated postsynaptic signaling to opiate and alpha 2-adrenergic analgesia and analgesic sex differences. 1249 46


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