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)

Calcitonin gene-related peptide (CGRP) is expressed at high levels in roughly 50% of spinal sensory neurons and plays a role in peripheral vasodilation as well as nociceptive signalling in the spinal cord. Spinal motoneurons express low levels of CGRP; motoneuronal CGRP is thought to be involved in end-plate plasticity and to have trophic effects on target muscle cells. As both sensory and motoneurons express receptors for glial cell line-derived neurotrophic factor (GDNF) we sought to determine whether CGRP was regulated by GDNF. Rats were treated intrathecally for 1-3 weeks with recombinant human GDNF or nerve growth factor (NGF) (12 microg/day) and dorsal root ganglia and spinal cords were stained for CGRP. The GDNF treatment not only increased CGRP immunoreactivity in both sensory and motoneurons but also resulted in hypertrophy of both populations. By combined in situ hybridization and immunohistochemistry we found that, in the dorsal root ganglia, CGRP was up-regulated specifically in neurons expressing GDNF but not NGF receptors following GDNF treatment. Despite the increase in CGRP in GDNF-treated rats, there was no increase in thermal or mechanical pain sensitivity, while NGF-treated animals showed significant decreases in pain thresholds. In motoneurons, GDNF increased the overall intensity of CGRP immunoreactivity but did not increase the number of immunopositive cells. As GDNF has been shown to promote the regeneration of both sensory and motor axons, and as CGRP appears to be involved in motoneuronal plasticity, we reason that at least some of the regenerative effects of GDNF are mediated through CGRP up-regulation.
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PMID:Glial cell line-derived neurotrophic factor increases calcitonin gene-related peptide immunoreactivity in sensory and motoneurons in vivo. 1465 20

Visceral pain is the most common form of pain produced by disease and is thus of interest in the study of gastrointestinal (GI) complaints such as irritable bowel syndrome, in which sensory signals perceived as GI pain travel in extrinsic afferent neurones with cell bodies in the dorsal root ganglia (DRG). The DRG from which the primary spinal afferent innervation of the mouse descending colon arises are not well defined. This study has combined retrograde labelling and immunohistochemistry to identify and characterize these neurones. Small to medium-sized retrogradely labelled cell bodies were found in the DRG at levels T8-L1 and L6-S1. Calcitonin gene-related peptide (CGRP)- and P2X3-like immunoreactivity (LI) was seen in 81 and 32%, respectively, of retrogradely labelled cells, and 20% bound the Griffonia simplicifolia-derived isolectin IB4. CGRP-LI and IB4 were co-localized in 22% of retrogradely labelled cells, whilst P2X3-LI and IB4 were co-localized in 7% (vs 34% seen in the whole DRG population). Eighty-two per cent of retrogradely labelled cells exhibited vanilloid receptor 1-like immunoreactivity (VR1-LI). These data suggest that mouse colonic spinal primary afferent neurones are mostly peptidergic CGRP-containing, VR1-LI, C fibre afferents. In contrast to the general DRG population, a subset of neurones exist that are P2X3 receptor-LI but do not bind IB4.
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PMID:Characterization of the primary spinal afferent innervation of the mouse colon using retrograde labelling. 1476 11

There now is one realized and several attractive targets for the treatment of acute attacks of migraine that will follow and augment the use of serotonin 5-HT1B/1D receptor agonists, the triptans. Calcitonin gene-related peptide (CGRP) receptor blockade recently has been shown to be an effective acute antimigraine strategy; therefore, blockade of CGRP release by inhibition of trigeminal nerves would seem a logical approach. A number of targets are reviewed in this article including serotonin 5-HT1F and 5-HT1D receptors, adenosine A1 receptors, nociceptin, vanilloid TRPV1 receptors, and anandamide CB1 receptors. Development of one or more such compound offers the exciting prospect of new non-vasoconstrictor treatments for migraine and cluster headache.
Curr Pain Headache Rep 2004 Oct
PMID:Post-triptan era for the treatment of acute migraine. 1536 24

Calcitonin gene-related peptide (CGRP), acting through CGRP receptors, produces behavioral signs of mechanical hyperalgesia in rats and sensitization of wide dynamic range (WDR) neurons in the spinal cord dorsal horn. Although involvement of CGRP receptors in central sensitization has been confirmed, the second-messenger systems activated by CGRP receptor stimulation and involved in pain transmission are not clear. This study tested whether the hyperalgesia and sensitizing effects of CGRP receptor activation on WDR neurons are mediated by protein kinase A or C (PKA or PKC) signaling. Intrathecal injection of CGRP in rats produced mechanical hyperalgesia, as shown by paw withdrawal threshold tests. CGRP-induced hyperalgesia was attenuated significantly by the CGRP1 receptor antagonist, CGRP8-37. The effect was also attenuated significantly by a PKA inhibitor (H89) or a PKC inhibitor (chelerythrine chloride). Electrophysiological experiments demonstrated that superfusion of the spinal cord with CGRP-induced sensitization of spinal dorsal horn neurons. The CGRP effect could be blocked by CGRP8-37. Either a PKA or PKC inhibitor (H89 or chelerythrine) also attenuated this effect of CGRP. These results are consistent with the hypothesis that CGRP produces hyperalgesia by a direct action on CGRP1 receptors in the spinal cord dorsal horn and suggest that the effects of CGRP are mediated by both PKA and PKC second-messenger pathways.
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PMID:Calcitonin gene-related peptide receptor activation produces PKA- and PKC-dependent mechanical hyperalgesia and central sensitization. 1548 24

We explored the specific impact of polyol pathway hyperactivity on dorsal root ganglia (DRG) using transgenic mice that overexpress human aldose reductase because DRG changes are crucial for the development of diabetic sensory neuropathy. Littermate mice served as controls. Half of the animals were made diabetic by streptozotocin injection and followed for 12 weeks. After diabetes onset, diabetic transgenic mice showed a significant elevation of pain sensation threshold after transient decrease and marked slowing of motor and sensory nerve conduction at the end of the study, while these changes were modest in diabetic littermate mice. Protein kinase C (PKC) activities were markedly reduced in diabetic transgenic mice, and the changes were associated with reduced expression of membrane PKC-alpha isoform that was translocated to cytosol. Membrane PKC-betaII isoform expression was contrariwise increased. Calcitonin gene-related peptide-and substance P-positive neurons were reduced in diabetic transgenic mice and less severely so in diabetic littermate mice. Morphometric analysis disclosed neuronal atrophy only in diabetic transgenic mice. Treatment with an aldose reductase inhibitor (fidarestat 4 mg x kg(-1) x day(-1), orally) corrected all of the changes detected in diabetic transgenic mice. These findings underscore the pathogenic role of aldose reductase in diabetic sensory neuropathy through the altered cellular signaling and peptide expressions in DRG neurons.
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PMID:Effects of polyol pathway hyperactivity on protein kinase C activity, nociceptive peptide expression, and neuronal structure in dorsal root ganglia in diabetic mice. 1556 56

Vertebral collapse is one of the most common fractures associated with osteoporosis. The subsequent back pain is severe and often requires medications, bed rest and hospitalization to control pain and improve mobilization. The purpose of this systematic review was to assess the effects of calcitonin versus placebo for the treatment of acute pain in patients sustaining stable, recent, osteoporotic vertebral compression fractures. MEDLINE (1966-2003), EMBASE (1980-2003), Cochrane Controlled Trial Registry (2003, volume 3), other databases, and conference proceedings were searched for relevant research. Primary study authors and the pharmaceutical manufacturer were contacted, and bibliographies of relevant papers were hand-searched. Randomized, double-blind, placebo-controlled trials comparing calcitonin versus placebo for the acute pain of recent osteoporotic vertebral compression fractures were included. Two reviewers extracted data, performed numeric calculations and extrapolated graphical data independently. The combined results from five randomized controlled trials, involving 246 patients, determined that calcitonin significantly reduced the severity of pain using a visual analogue scale following diagnosis. Pain at rest was reduced as early as 1 week into treatment (weighted mean difference [WMD] =3.08; 95% confidence interval [CI]: 2.64, 3.52) and this effect continued weekly to 4 weeks (WMD =4.03; 95% CI: 3.70, 4.35). A similar pattern was seen for pain scores associated with sitting, standing, and walking. Side effects were gastrointestinal, minor and often self-limited. Calcitonin appears to be effective in the management of acute pain associated with acute osteoporotic vertebral compression fractures by shortening time to mobilization.
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PMID:Calcitonin for treating acute pain of osteoporotic vertebral compression fractures: a systematic review of randomized, controlled trials. 1561 41

Quality of life (QOL) is impaired in patients with osteoporosis, to which bodily pain greatly contributes. The presence of vertebral fractures detrimentally affects the patients' QOL in a dose-dependent manner. Calcitonin, with its potent analgesic action, markedly improves the various aspects of patients' QOL. Efficacy for the treatment of osteoporosis should be evaluated in terms of QOL also, in addition to the increase in bone mineral density and fracture prevention.
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PMID:[Improvement of QOL in osteoporotic patients by calcitonin treatment]. 1574 99

Corticosteroid-induced osteoporosis is the leading cause of secondary osteoporosis and a significant cause of morbidity in both men and women. Long-term use of even low-dose corticosteroids has been associated with increased risk of bone loss. Recent large randomized controlled trials have generated new knowledge on treatment strategies for patients with corticosteroid-induced osteoporosis. However, the majority of individuals receiving corticosteroids are not receiving prophylaxis for osteoporosis. Calcium and vitamin D should be recommended to patients initiating therapy with corticosteroids (and should be adequate for those receiving corticosteroids for less than 3 months). For those receiving corticosteroids for greater than 3 months, bisphosphonates are the therapy of choice, with both alendronate (alendronic acid) and risedronate (risedronic acid) approved by the US FDA for use in this indication. Calcitonin can be considered a second-line agent and should be reserved for patients who are intolerant of bisphosphonates or who are experiencing pain from a vertebral fracture. Hormone replacement therapy or testosterone therapy may be offered to those individuals on long-term corticosteroid treatment who are hypogonadal. Teriparatide (recombinant human parathyroid hormone 1-34) shows promise as a future anabolic agent for the prevention and treatment of patients with corticosteroid-induced osteoporosis.
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PMID:Corticosteroid-induced osteoporosis: a guide to optimum management. 1583 82

The etiology and pathogenesis of chronic tendon pain are unknown. Even though tendon biopsies having shown an absence of inflammatory cell infiltration, anti-inflammatory agents (non-steroidal anti-inflammatory drugs, corticosteroidal injections) are commonly used. We have demonstrated that it is possible to use intratendinous microdialysis to investigate human tendons, and found normal prostaglandin E2 (PGE2) levels in chronic painful tendinosis (Achilles and patellar) tendons. Furthermore, gene technological analyses of biopsies showed no upregulation of pro-inflammatory cytokines. These findings show that there is no PGE2-mediated intratendinous inflammation in the chronic stage of these conditions. The neurotransmitter glutamate (a potent modulator of pain in the central nervous system) was, for the first time, found in human tendons. Microdialysis showed significantly higher glutamate levels in chronic painful tendinosis (Achilles and patellar) tendons, compared with pain-free normal control tendons. The importance of this finding is under evaluation. Treatment is considered to be difficult, and not seldom, surgery is needed. However, recent researches on non-surgical methods have shown promising clinical results. Painful eccentric calf-muscle training has been demonstrated to give good clinical short- and mid-term results on patients with chronic painful mid-portion Achilles tendinosis. Good clinical results were associated with decreased tendon thickness and a structurally more normal tendon with no remaining neovessels. Using ultrasonography (US)+color Doppler (CD), and immunhistochemical analyses of biopsies, we have recently demonstrated a vasculo/neural (Substance-P and Calcitonin Gene-Related Peptide nerves) ingrowth in the chronic painful tendinosis tendon, but not in the pain-free normal tendon. A specially designed treatment, using US- and CD-guided injections of the sclerosing agent Polidocanol, targeting the neovessels outside the tendon, has been shown to cure tendon pain in pilot studies, in a majority of the patients. A recent, randomized, double-blind study verified the importance of injecting the sclerosing substance Polidocanol.
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PMID:The chronic painful Achilles and patellar tendon: research on basic biology and treatment. 1599 42

The epidermis is innervated by fine nerve endings that are important in the perception of nociceptive stimuli. However, their role in neuropathic pain is controversial. In this paper, changes in the innervation patterns of epidermal sensory afferent fibres in the rat lower lip have been studied following bilateral chronic constriction injury (CCI) of the mental nerve-a purely sensory branch of the trigeminal nerve. Sections of the lower lip were processed for immunocytochemistry using antibodies against Protein Gene Product (PGP) 9.5 and Calcitonin Gene-Related Peptide (CGRP) to identify the non-peptidergic and the peptidergic populations of nociceptive small diameter primary sensory afferent fibres. Peptidergic fibres co-localised both markers and the non-peptidergic fibres only stained for PGP 9.5 and not for CGRP. We quantified the total fibre length per 6000 microm(2) in the epidermis at several time points following CCI. Our data indicate that both fibre populations were significantly decreased at 2 weeks post-CCI, followed by fibre re-growth at levels above those seen in sham-operated animals at 4 weeks; however, this increase was only statistically significant for the non-peptidergic population. At 8 weeks post-CCI, the fibre lengths of both populations did not differ significantly from shams. This transient hyper-innervation of the epidermis by one subpopulation of nociceptive fibres coincided with the occurrence of spontaneous pain or dysesthetic sensations which we detected in a previous study in the same animal model. Therefore, we speculate that this transient hyper-innervation of the epidermis following injury could play a role in nociception in these animals.
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PMID:Changes in nociceptive sensory innervation in the epidermis of the rat lower lip skin in a model of neuropathic pain. 1613 29


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