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)

Novel findings of changes in nociceptive dorsal root ganglion (DRG) neurons during hindlimb inflammation induced by complete Freund's adjuvant (CFA) injections in the hindpaw and hindleg are reported. These include increased maximum fiber following frequency in nociceptive C- and Adelta-fiber units by 2.7 and 3 times, respectively, and increased incidence of ongoing (spontaneous) activity by 3.3 times (to 54%) and 2.4 times (to 27%), respectively. These changes and the CFA-induced changes in somatic action potential (AP) configuration in nociceptive neurons (Djouhri and Lawson, 1999) were incomplete 24 hr after CFA. The nerve growth factor (NGF) dependence of the inflammation-induced changes was examined by injecting a synthetic NGF sequestering protein [tyrosine receptor kinase A Ig2 (trkA Ig2)] with CFA and subsequently into the CFA injection sites. NGF sequestration prevented some CFA-induced changes in nociceptive neurons including: the increased fiber following frequency (C and Adelta), the increased proportions of units with ongoing activity (C and Adelta), the decreased AP duration (C and Adelta), but not the decreased afterhyperpolarization (AHP) durations (C, Adelta, and Aalpha/beta) (Djouhri and Lawson, 1999). AP variables of nociceptive units with spontaneous activity were examined. The time course of electrophysiological changes in nociceptive units is consistent with processes involving altered protein expression and/or retrograde transport of factors. These results (1) implicate NGF in regulating inflammation-induced decreases in AP duration and in increases in firing rate and spontaneous activity but not in decreases in AHP duration and (2) suggest clinical advantages of reducing NGF in some inflammatory pain states.
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PMID:Time course and nerve growth factor dependence of inflammation-induced alterations in electrophysiological membrane properties in nociceptive primary afferent neurons. 1169 84

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare genetic disease characterized by absence of reaction to noxious stimuli and anhidrosis. The genetic bases of CIPA have remained long unknown. A few years ago, point mutations affecting both coding and noncoding regions of the neurotrophic tyrosine receptor kinase type 1 (NTRK1)/nerve growth factor receptor gene have been detected in CIPA patients, demonstrating the implication of the nerve growth factor/NTRK1 pathway in the pathogenesis of the disease. We have previously shown that two CIPA mutations, the G571R and the R774P, inactivate the NTRK1 receptor by interfering with the autophosphorylation process. We have extended our functional analysis to seven additional NTRK1 mutations associated with CIPA recently reported by others. Through a combination of biochemical and biological assays, we have identified polymorphisms and pathogenic mutations. In addition to the identification of residues important for NTRK1 activity, our analysis suggests the existence of two novel pathogenic mechanisms in CIPA: one based on the NTRK1 receptor processing and the other acting through the reduction of the receptor activity.
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PMID:Novel pathogenic mechanisms of congenital insensitivity to pain with anhidrosis genetic disorder unveiled by functional analysis of neurotrophic tyrosine receptor kinase type 1/nerve growth factor receptor mutations. 1171 21

During development, brain-derived neurotrophic factor (BDNF) supports the survival of certain neuronal population in central and peripheral nervous system. In adulthood, BDNF has been suggested to act as an important modulator of synaptic plasticity. This article reviews and discusses its potential role as neuromodulator in the spinal dorsal horn. BDNF is synthesized in the cell body of primary sensory neurons (pre-synaptic neurons) and its expression is regulated in models of inflammatory and neuropathic pain. The high affinity receptor for BDNF, tropomyosine receptor kinase B (TrkB), is expressed by post-synaptic neurons of the dorsal horn. Stimulation of pre-synaptic nociceptive afferent fibres induces BDNF release and consequent activation of TrkB receptors leading to a post-synaptic excitability. Electrophysiological recordings showed that BDNF enhances the ventral root potential induced by C-fibre stimulation in an in vitro preparation. In addition, behavioural data indicate that antagonism of BDNF attenuates the second phase of hyperalgesia induced by formalin (in nerve growth factor-treated animals) and the thermal hyperalgesia induced by carageenan, suggesting that BDNF is involved in some aspects of central sensitisation in conditions of peripheral inflammation. In conclusion, BDNF meets many of the criteria necessary to define it as a neurotransmitter/neuromodulator in small diameter nociceptive neurons.
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PMID:BDNF: a neuromodulator in nociceptive pathways? 1258 22

The purpose of this study was to characterize the impact of tooth injury on the distribution of tyrosine receptor kinase B (TrkB) among trigeminal ganglion neurons and assess the time course for tooth injury-induced TrkB distribution changes. In addition, we sought to further characterize the subpopulation of the afferents expressing TrkB receptors. Fifteen adult male Sprague-Dawley rats were studied. Pulpal inflammation was induced and ganglia were subsequently harvested and processed at different time points. Standard immunohistochemical fluorescence techniques were used to visualize TrkB-like immunoreactivity and isolectin B4 binding. Results indicate that full-length TrkB receptors are present in 36.6% of trigeminal ganglion neurons. This percentage decreases for the first 48 h and then increases to 41% by 7 days after tooth injury. Finally, TrkB appears to be present in a large percentage (54%) of isolectin B4+ neurons, suggesting that it is present in nociceptive afferents. These data highlight the fact that even mild injury results in sustained changes in nociceptive circuitry and raise the possibility that the brain-derived neurotrophic factor/TrkB system may contribute to persistent pain after tooth repair.
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PMID:Changes in TrkB-like immunoreactivity in rat trigeminal ganglion after tooth injury. 1259 15

Release of endogenous dynorphin opioids within the spinal cord after partial sciatic nerve ligation (pSNL) is known to contribute to the neuropathic pain processes. Using a phosphoselective antibody [kappa opioid receptor (KOR-P)] able to detect the serine 369 phosphorylated form of the KOR, we determined possible sites of dynorphin action within the spinal cord after pSNL. KOR-P immunoreactivity (IR) was markedly increased in the L4-L5 spinal dorsal horn of wild-type C57BL/6 mice (7-21 d) after lesion, but not in mice pretreated with the KOR antagonist nor-binaltorphimine (norBNI). In addition, knock-out mice lacking prodynorphin, KOR, or G-protein receptor kinase 3 (GRK3) did not show significant increases in KOR-P IR after pSNL. KOR-P IR was colocalized in both GABAergic neurons and GFAP-positive astrocytes in both ipsilateral and contralateral spinal dorsal horn. Consistent with sustained opioid release, KOR knock-out mice developed significantly increased tactile allodynia and thermal hyperalgesia in both the early (first week) and late (third week) interval after lesion. Similarly, mice pretreated with norBNI showed enhanced hyperalgesia and allodynia during the 3 weeks after pSNL. Because sustained activation of opioid receptors might induce tolerance, we measured the antinociceptive effect of the kappa agonist U50,488 using radiant heat applied to the ipsilateral hindpaw, and we found that agonist potency was significantly decreased 7 d after pSNL. In contrast, neither prodynorphin nor GRK3 knock-out mice showed U50,488 tolerance after pSNL. These findings suggest that pSNL induced a sustained release of endogenous prodynorphin-derived opioid peptides that activated an anti-nociceptive KOR system in mouse spinal cord. Thus, endogenous dynorphin had both pronociceptive and antinociceptive actions after nerve injury and induced GRK3-mediated opioid tolerance.
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PMID:Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance. 1514 Sep 29

Molecular mechanisms underlying C-fiber stimulation-induced ERK (extracellular signal-regulated kinase) activation in dorsal horn neurons and its contribution to central sensitization have been investigated. In adult rat spinal slice preparations, activation of C-fiber primary afferents by a brief exposure of capsaicin produces an eightfold to 10-fold increase in ERK phosphorylation (pERK) in superficial dorsal horn neurons. The pERK induction is reduced by blockade of NMDA, AMPA/kainate, group I metabotropic glutamate receptor, neurokinin-1, and tyrosine receptor kinase receptors. The ERK activation produced by capsaicin is totally suppressed by inhibition of either protein kinase A (PKA) or PKC. PKA or PKC activators either alone or more effectively together induce pERK in superficial dorsal horn neurons. Inhibition of calcium calmodulin-dependent kinase (CaMK) has no effect, but pERK is reduced by inhibition of the tyrosine kinase Src. The induction of cAMP response element binding protein phosphorylation (pCREB) in spinal cord slices in response to C-fiber stimulation is suppressed by preventing ERK activation with the MAP kinase kinase inhibitor 2-(2-diamino-3-methoxyphenyl-4H-1-benzopyran-4-one (PD98059) and by PKA, PKC, and CaMK inhibitors. Similar signaling contributes to pERK induction after electrical stimulation of dorsal root C-fibers. Intraplantar injection of capsaicin in an intact animal increases expression of pCREB, c-Fos, and prodynorphin in the superficial dorsal horn, changes that are prevented by intrathecal injection of PD98059. Intrathecal PD98059 also attenuates capsaicin-induced secondary mechanical allodynia, a pain behavior reflecting hypersensitivity of dorsal horn neurons (central sensitization). We postulate that activation of ionotropic and metabotropic receptors by C-fiber nociceptor afferents activates ERK via both PKA and PKC, and that this contributes to central sensitization through post-translational and CREB-mediated transcriptional regulation in dorsal horn neurons.
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PMID:Ionotropic and metabotropic receptors, protein kinase A, protein kinase C, and Src contribute to C-fiber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization. 1538 14

Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal recessive disorder caused by mutations in the neurotrophic tyrosine receptor kinase 1 (NTRK1) gene which encodes the receptor for nerve growth factor (NGF). We report the clinical course in three sibs with CIPA and proven NTRK1 gene mutations with a follow-up over a 25-year period in one of them. They had the characteristic clinical features of an abnormally high pain threshold, and mental retardation; in addition their clinical course was marked by the occurrence of early onset renal disease with recurrent microhematuria and proteinuria and frequent observations of increased serum creatinine and blood urea levels. Light microscopy study of a renal biopsy performed in one of them at age of 20 months showed focal glomerulosclerosis, interstitial fibrosis and tubular atrophy. This patient and his younger brother died because of renal failure at the age of 25 years and 14 years, respectively. The sister still alive showed renal impairment and deep venous thrombosis associated with lupus anticoagulant activity, decrease of circulating autoreactive CD5 (+) B lymphocytes and increased urinary levels of IgG and kappa and lambda light chains, suggesting a possible defect in regulation of B-lymphocyte function. In the light of the NGF-related molecular defect, the extraneurological tissue involvement in CIPA might in part reflect dysregulation of immune mechanisms which possibly brings about a chronic inflammatory response. This, in turn, could result in renal disease which should be mentioned among the life-threatening complications associated with this disorder.
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PMID:Congenital insensitivity to pain with Anhidrosis (NTRK1 mutation) and early onset renal disease: clinical report on three sibs with a 25-year follow-up in one of them. 1613 53

Biochemical studies have shown that domain 5 of the TrkA (tropomyosin receptor kinase A) receptor is involved in the binding of NGF (nerve growth factor). Crystallographic studies have confirmed this, demonstrating that one homodimer of NGF binds to two TrkAd5 molecules. TrkAd5 has been made recombinantly in Escherichia coli, purified and shown to bind NGF with picomolar affinity. We have used the co-ordinates of the crystal structure of the NGF-TrkAd5 complex to screen approximately two million compounds in silico for the identification of small molecule agonists/antagonists. Selected hits were shown to be active in an in vitro ligand-binding assay; structure-activity relationships are now being investigated. In addition, TrkAd5 has been shown to be efficacious in preclinical models of inflammatory pain and asthma by the sequestration of excess levels of endogenous NGF, and therefore represents a novel therapeutic agent.
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PMID:NGF receptor TrkAd5: therapeutic agent and drug design target. 1685 68

Nerve growth factor (NGF) regulates sensory neuron phenotype by elevated expression of ion channels and receptors contributing to pain. Peripheral opioid antinociception is dependent on sensory neuron mu opioid receptor (MOR) expression, coupling and efficacy. This study investigates the role of NGF in the upregulation of the number and efficacy of sensory MORs rendering sites of painful inflammation more susceptible to opioids. We identified co-localization of MOR with calcitonin gene-related peptides (CGRP) and with the NGF receptors tyrosine receptor kinase (TrkA) and p75(NTR) within rat dorsal root ganglia (DRG). We showed that unilateral hind paw inflammation induced with Freund's complete adjuvant (FCA) or intraplantar (i.pl.) NGF increased NGF's retrograde transport and MOR expression in TrkA positive DRG which was prevented by the disruption of this NGF transport. MOR upregulation in DRG was followed by enhanced axonal MOR transport towards peripheral nerve terminals and subsequent increase of MOR-ir nerve fibres within skin. Furthermore, peripheral antinociception elicited by i.pl. fentanyl was naloxone reversible and potentiated exclusively in inflamed and NGF-treated paws. Both FCA- and NGF-induced effects occurring through DRG to peripheral nerve fibres and the potentiation of antinociception were abrogated by NGF neutralization. Therefore, our results suggest that NGF not only contributes to inflammatory pain but also governs the upregulation in the number and efficacy of sensory neuron MOR, resulting in enhanced opioid susceptibility towards better pain control. This suggests the potential to overcome the unresponsiveness to opioids of certain neuropathic pain states.
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PMID:Nerve growth factor governs the enhanced ability of opioids to suppress inflammatory pain. 1714 30

Calcitonin gene-related peptide (CGRP) increases in sensory neurons after inflammation and plays an important role in abnormal pain responses, but how this neuropeptide is regulated is not well understood. Both activin A and nerve growth factor (NGF) increase in skin after inflammation and induce CGRP in neurons in vivo and in vitro. This study was designed to understand how neurons integrate these two signals to regulate the neuropeptide important for inflammatory pain. In adult dorsal root ganglion neurons, NGF but not activin alone produced a dose-dependent increase in CGRP mRNA. When added together with NGF, activin synergistically increased CGRP mRNA, indicating that sensory neurons combine these signals. Studies were then designed to learn if that combination occurred at a common receptor or shared intracellular signals. Studies with activin IB receptor or tyrosine receptor kinase A inhibitors suggested that each ligand required its cognate receptor to stimulate the neuropeptide. Further, activin did not augment NGF-initiated intracellular mitogen-activated protein kinase signals but instead stimulated Smad phosphorylation, suggesting these ligands initiated parallel signals in the cytoplasm. Activin synergy required several NGF intracellular signals to be present. Because activin did not further stimulate, but did require NGF intracellular signals, it appears that activin and NGF converge not in receptor or cytoplasmic signals, but in transcriptional mechanisms to regulate CGRP in rat sensory neurons after inflammation.
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PMID:Activin acts with nerve growth factor to regulate calcitonin gene-related peptide mRNA in sensory neurons. 1796 31


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