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)

Galanin is a neuroendocrine peptide that modulates many different normal physiological effects including memory, weight, and pain perception. To better understand galanin receptor function, we cloned and characterized the galanin-1 receptor (GALN1R) gene isolated from a human P1 library. We determined that this gene contains 2 introns of approximately 2.1 and 2.9 Kb, both of which are located in the 3rd intracellular loop. We identified transcriptional initiation sites 61 and 63 bp upstream of the translation initiation codon ATG. Sequencing of the GALN1R gene 5' flanking region revealed it to be GC rich and devoid of TATA or CCAAT boxes, features of housekeeping genes. To identify potential sites regulating promoter activity, variable lengths of the 5' flanking region were fused to a CAT gene and studied in Bowes human melanoma cells. Significant losses in CAT activity were observed only with the elimination of 2 NF-kappa B sites, located -269 and -809 bp upstream from the translational start site, respectively. These findings suggest the novel possibility that GALN1R gene expression may be regulated as a consequence of inflammatory conditions. Finally fluorescent in situ hybridization (FISH) assigned this gene to chromosome 15q24.
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PMID:Cloning, chromosomal location, and transcriptional regulation of the human galanin-1 receptor gene (GALN1R). 942 10

Chronic polyarthritis due to complete Freund's adjuvant injection is characterized by severe inflammation and pain. In the present immunocytochemical and in situ hybridization study on the rat, we quantitatively investigated peptide and peptide messenger RNA expression in the sensory circuit at the spinal level, i.e. sensory neurons in the dorsal root ganglia and in nerve endings and local neurons in the dorsal horn of the spinal cord. The immunocytochemical experiments were carried out five, 13 and 21 days after complete Freund's adjuvant injection, whereas in situ hybridization study was performed after 21 days from complete Freund's adjuvant injection. The main results in the present study are the following: (i) a decrease in substance P-, calcitonin gene-related peptide- and galanin-like immunoreactivities in dorsal root ganglia is observed five days after complete Freund's adjuvant injection, with recovery (calcitonin gene-related peptide and galanin) or even an increase (substance P) after 21 days; (ii) calcitonin gene-related peptide, substance P and galanin peptide levels are increased in dorsal root ganglia after 21 days; (iii) opioid peptide (enkephalin and dynorphin), substance P and galanin messenger RNAs are strongly up-regulated in dorsal horn neurons after 21 days; (iv) neuropeptide Y content increases in dorsal root fibres and neuropeptide Y messenger RNA levels decrease in spinal neurons after 21 days; and (v) a dramatic decrease in calcitonin gene-related peptide and cholecystokinin messenger RNA levels is found in motoneurons in the ventral horn after 21 days. These data indicate that peptide expression in dorsal root ganglia and the spinal cord is markedly influenced by severe inflammation with distinct and individual temporal patterns, which are also related to the severe rearrangement of joint structure during polyarthritis. The increase in galanin levels in dorsal root ganglia 21 days after complete Freund's adjuvant injection can be related to the structural damage of nerve fibres. Thus, there may be a transition from inflammatory to neuropathic pain, which could have consequences for treatment of patients with rheumatoid arthritis.
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PMID:Peptide plasticity in primary sensory neurons and spinal cord during adjuvant-induced arthritis in the rat: an immunocytochemical and in situ hybridization study. 946 62

The lumbar 5 (L5) dorsal root ganglia (DRGs) were studied in neuropeptide tyrosine (NPY)-deficient (-/-) and wild type (+/+) mice after unilateral sciatic nerve transection using in situ hybridization and immunohistochemistry. NPY, galanin and two NPY receptors (Y-Rs) were analyzed as well as self-mutilation behaviour (autotomy) and nociceptive thresholds. No difference between wild type and NPY-deficient mice was seen in the tail-flick or hot plate test. However, -/- mice showed a much stronger autotomy behaviour than wild type mice. NPY was not found in L5 DRGs in -/- mice, not even after axotomy. Galanin was upregulated to the same extent after axotomy in NPY-deficient and wild type mice. Y1- and Y2-R mRNAs were found mainly in small DRG neuron profiles. Both receptor mRNAs were downregulated after axotomy, to about the same extent in NPY-deficient as in wild type mice. In control and contralateral ganglia the mRNA levels of both receptors were lower in NPY-deficient mice than in wild type mice. The contralateral Y2-R mRNA levels did not reach control values in the NPY-deficient mice, as they did in the wild type mice. In both strains the Y1-R protein was decorating the somatic plasmalemma. The present results suggest that lack of NPY may cause exaggerated autotomy, a self-mutilation behaviour possibly related to pain sensation, in agreement with the described analgesic effect of NPY. Although significant differences in levels of Y1- and especially Y2-R mRNAs were observed between wild type and NPY-deficient mice, they were only moderate. These findings suggest that expression, regulation, localization and possible function of Y1- and Y2-Rs are not dependent on presence of the endogenous ligand. Also, deletion of NPY does not seem to influence the expression of the partly coexisting peptide galanin.
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PMID:Effect of peripheral axotomy on dorsal root ganglion neuron phenotype and autonomy behaviour in neuropeptide Y-deficient mice. 980 5

Nerve injury can lead to sympathetically dependent neuropathic pain. A possible site of sympathetic-sensory interaction is the dorsal root ganglion (DRG), where sympathetic axons form pericellular 'baskets' around a subpopulation of DRG neurons. Since these structures possibly represent functional units of sympathetic pain, we attempted to characterize the neuropeptidergic phenotype of basketed DRG neurons. We performed double-labeling immunohistochemistry for tyrosine hydroxylase and neuropeptides on DRG sections, 2 weeks following L5 spinal nerve ligation (a well-characterized animal model of sympathetic pain). We found that basketed DRG neurons typically do not contain substance P, calcitonin gene-related peptide, galanin, neuropeptide tyrosine, or vasoactive intestinal polypeptide, and we conclude that if sympathetic baskets contribute to neuropathic pain, the involvement of these neuropeptides is unimportant.
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PMID:Sympathetic axons surround neuropeptide-negative axotomized sensory neurons. 980 25

The galanin neuropeptide system is widely distributed throughout the brain and periphery and is thought to play a role in feeding, pain and reproduction. To evaluate the human galanin receptor 1 as a potential therapeutic target, we fully characterized its interaction with several galanin-like peptides. The human galanin receptor 1 receptor was stably expressed using an episomal system in human embryonic kidney 293E cells. Saturation isotherms using 125I-human galanin revealed two distinct populations of receptor affinity states in membranes and whole cells with picomolar and nanomolar affinities at the high- and low affinity states, respectively. A scintillation proximity assay revealed that 125I-human galanin binding in membranes reached steady-state within 2 to 2.5 hr; however, only 50% of galanin radiolabel dissociated from the receptors by excess galanin or guanosine 5'-O-3-thiotriphosphate even after 20 hr. In contrast, galanin binding in whole cells was completely reversible within 1 hr. Competition binding assays showed that galanin-like peptides bound with picomolar affinities in membranes and whole cells. These peptides behaved as full agonists as determined by the inhibition of forskolin-stimulated cyclic 3'5'-adenosine monophosphate production and the stimulation of guanosine 5'-O-(3-[35S]thiotriphosphate binding. The agonist profile of M40, a representative chimeric peptide, was found not to be the result of receptor reserve because receptor inactivation by partial alkylation experiments confirmed its full intrinsic efficacy under conditions of a "zero" reserve state. These observations suggest that the antagonist effects in vivo of M40, and perhaps other chimeric peptides, are not mediated via direct interactions with the galanin receptor 1 receptor.
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PMID:Pharmacological and biochemical characterization of a recombinant human galanin GALR1 receptor: agonist character of chimeric galanin peptides. 980 67

We examined two possible mechanisms of neuropathic pain: contribution of adjacent intact nerves and decrease in presynaptic inhibition at the central terminal of the injured primary afferent. To this end, we examined the effects of unilateral L5 spinal nerve ligation, which causes mechanical allodynia and heat hyperalgesia in the ipsilateral hind paw, on gene expression in L4 and L5 dorsal root ganglion (DRG) neurons using in situ hybridization (ISH). Specifically, we examined changes in the expression of messenger RNAs (mRNAs) for neuropeptides which have been reported to be up- or down-regulated in the axotomized DRG neurons and for gamma-aminobutyric acid (GABA)A receptor (GABA(A)-R) subunits which contribute to presynaptic inhibition at the primary afferent terminals. Seven days following ligation, ISH demonstrated an increase in signal intensity for calcitonin gene-related peptide (CGRP) mRNA in the subpopulation of small-to medium-sized L4 DRG neurons ipsilateral to the ligation which were not directly injured as compared to the contralateral side, although the overall percentages and the size distribution of positively labelled neurons for CGRP mRNA were not different between the bilateral L4 DRGs. This suggests that the L4 DRG neurons which express CGRP mRNA constitutively up-regulated the gene expression and the functional importance of these neurons has increased following L5 spinal nerve ligation. However, the mRNAs for other neuropeptides such as preprotachykinin (PPT), vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), and galanin (GAL), were not different between the bilateral L4 DRGs. The mRNA for the GABA(A)-Rgamma2 subunit was significantly down-regulated in the medium- to large-sized L5 DRG neurons ipsilateral to the ligation as compared to the contralateral side. GABA(A)-Ralpha2 subunit mRNA also decreased in the ipsilateral L5 DRG neurons but did not reach statistical significance. There was no difference in mRNAs between the bilateral L4 DRGs. These data suggest that the presynaptic disinhibition of the ipsilateral L5 primary afferent terminals may be explained at least partly by the down-regulation of GABA(A)-R following L5 spinal nerve ligation. Thus, both the up-regulation of CGRP in adjacent intact nerves and the decrease in presynaptic inhibition at the central terminal of the injured primary afferent could cause the hyper-excitability of dorsal horn neurons and contribute to the molecular mechanisms of this neuropathic pain model.
Pain 1998 Oct
PMID:Change in mRNAs for neuropeptides and the GABA(A) receptor in dorsal root ganglion neurons in a rat experimental neuropathic pain model. 982 8

Galanin is a 29/30 amino acids long neuroendocrine peptide, acting as an inhibitory modulator in the spinal cord. Several studies show that galanin is involved in control of pain threshold and acts synergistically with morphine, hence, inhibition of galanin degradation may be a pharmaceutical target for treatment of pain. In this study we have designed an 11 amino acids long substrate based on the first 10 N-terminal amino acids of galanin (this part contains the major pharmacophores of galanin), with a N-terminal fluorescent marker, anthranilic acid, and a C-terminal internal fluorescence quencher, 3-nitrotyrosine, coupled to the epsilon-amino group of the linker Lys11. Using this substrate to detect galanin degradation, we have purified a membrane bound galanin inactivating metallo-peptidase from bovine spinal cord. This enzyme, cleaving galanin between Trp2 and Thr3, is a novel 70 kDa, Zn2+ dependent metallo-peptidase.
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PMID:Purification of a galanin degrading 70 kDa metallo-peptidase from bovine spinal cord. 984 7

We have determined if peripheral nerve stimulation altered the increased spontaneous release of immunoreactive (ir)-galanin that is found in the superficial dorsal horn of the spinal cord of neuropathic rats. Using the antibody microprobe technique to study the localized sites of ir-galanin release in vivo, we found that high intensity electrical stimulation of the injured nerve resulted in a further increase in ir-galanin release in the superficial dorsal horn, with no significant persistence of ir-galanin after release. Release of ir-galanin at stimulus strengths sufficient to activate C fibres, in an area of the spinal cord thought to be concerned with nociceptive transmission, indicates a possible role for this peptide in the spinal modulation of pain after peripheral nerve injury.
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PMID:Primary afferent-evoked release of immunoreactive galanin in the spinal cord of the neuropathic rat. 986 Nov 37

The 29 amino acid neuropeptide galanin is widely distributed in the nervous and endocrine systems; highest levels of galanin synthesis and storage occur within the hypothalamus in the median eminence, but it is also abundantly expressed in the basal forebrain, the peripheral nervous system, and gut. To further define the role played by galanin in the peripheral nervous and endocrine systems, a mouse strain carrying a loss-of-function germ-line mutation of the galanin locus, engineered by targeted mutagenesis in embryonic stem cells, has been generated. The mutation removes the first five exons containing the entire coding region for the galanin peptide. Germ-line transmission of the disrupted galanin locus has been obtained, and the mutation has been bred to homozygosity on the inbred 129O1aHsd background. Phenotypic analysis of mice lacking a functional galanin gene demonstrate that these animals are viable, grow normally, and can reproduce. A marked reduction in both the anterior pituitary prolactin content and in circulating plasma levels of the hormone is evident. Lactation is abolished along with abrogation of the proliferative response of the lactotroph to estrogen. The responses of sensory neurons to injury in the mutants are markedly impaired. Peripheral nerve regeneration is reduced with associated long-term functional deficits. There is a striking reduction in the development of chronic neuropathic pain. These two phenotypic changes may be explained, in part, by the observation that a subset of dorsal root ganglion neurons is lost in the mutant animals, implying a role for galanin as a trophic cell survival factor. These initial findings have important implications for our understanding and potential therapeutic treatment of (a) sensory nerve regeneration and neuropathic pain and (b) disordered pituitary proliferation and the development of prolactinoma.
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PMID:Targeted disruption of the murine galanin gene. 992 57

Galanin-like immunoreactivity and galanin receptors are found in dorsal root ganglion (DRG) cells and in dorsal horn interneurons, suggesting that this neuropeptide may have a role in sensory transmission and modulation at the spinal level. Expression of galanin or galanin receptors in the DRG and spinal cord are altered, sometimes in a dramatic fashion, by peripheral nerve injury or inflammation. Under normal conditions, galanin occurs in a small population of primary sensory neurons as well as in spinal interneurons. However, following peripheral nerve injury or inflammation, expression of galanin in primary afferents and spinal cord is upregulated. We examined the role of galanin in spinal processing of nociceptive information under normal and pathologic conditions in a large series of electrophysiologic and behavioral studies. Results suggest that under normal conditions galanin exerts tonic inhibition of nociceptive input to the central nervous system. After peripheral nerve injury the inhibitory control exerted by endogenous galanin, probably released from DRG neurons, is increased. During inflammation, galanin presumably released from dorsal horn interneurons also exerts an inhibitory function. Thus, stable galanin agonists may be useful in the treatment of inflammatory and neuropathic pain.
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PMID:Galanin in somatosensory function. 992 84


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