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)

Tetramethylpyrazine (TMP) is one of the alkaloids contained in Ligustrazine which has been used in traditional Chinese medicine as an analgesic for injury and dysmenorrhea. ATP can elicit the sensation of pain. This study observed the effects of TMP on ATP-activated current (IATP) in rat DRG neurons. TMP (0.1-1 mM) concentration-dependently inhibited ATP (100 microM)-activated current in rat DRG neurons. The inhibitory time of ATP (100 microM)-activated current appeared at 15 s after preapplication of TMP and reached its peak at about 45 s. The dose-response curves for IATP in the absence and presence of 1 mM TMP showed that TMP (1 mM) shifted the concentration-response curve of IATP downward markedly and the two EC50 values were very close (75 vs. 82 microM), while the threshold value remained unchanged. Therefore, the inhibitory effect of TMP on IATP may be noncompetitive. TMP did not alter the reversal potential (0 mV) of ATP-activated current, indicating that the site of TMP action is on or near the exterior surface of channel protein and not within the channel pore. Externally applied TMP (1 mM) increases the inhibitory effect of chelerythrine (PKC inhibitor) contained in pipette solution on IATP. The site of TMP action may be the binding of TMP to an allosteric site on the large extracellular region of ATP receptor-ion channel complex (P2X receptors) or PKC site of the N-terminus of P2X receptors. The mechanism of TMP action may be the allosteric regulation via acting on the large extracellular region of ATP receptor-ion channel complex (P2X receptors) and promoting the phosphorylation of PKC site of the N-terminus of P2X receptors.
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PMID:Tetramethylpyrazine inhibits ATP-activated currents in rat dorsal root ganglion neurons. 1580 30

Prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2) are major inflammatory mediators that play important roles in pain sensation and hyperalgesia. The role of their receptors (EP and IP, respectively) in inflammation has been well documented, although the EP receptor subtypes involved in this process and the underlying cellular mechanisms remain to be elucidated. The capsaicin receptor TRPV1 is a nonselective cation channel expressed in sensory neurons and activated by various noxious stimuli. TRPV1 has been reported to be critical for inflammatory pain mediated through PKA- and PKC-dependent pathways. PGE2 or PGI2increased or sensitized TRPV1 responses through EP1 or IP receptors, respectively predominantly in a PKC-dependent manner in both HEK293 cells expressing TRPV1 and mouse DRG neurons. In the presence of PGE2 or PGI2, the temperature threshold for TRPV1 activation was reduced below 35 degrees C, so that temperatures near body temperature are sufficient to activate TRPV1. A PKA-dependent pathway was also involved in the potentiation of TRPV1 through EP4 and IP receptors upon exposure to PGE2 and PGI2, respectively. Both PGE2-induced thermal hyperalgesia and inflammatory nociceptive responses were diminished in TRPV1-deficient mice and EP1-deficient mice. IP receptor involvement was also demonstrated using TRPV1-deficient mice and IP-deficient mice. Thus, the potentiation or sensitization of TRPV1 activity through EP1 or IP activation might be one important mechanism underlying the peripheral nociceptive actions of PGE2 or PGI2.
Mol Pain 2005 Jan 17
PMID:Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins. 1581 89

Recent findings indicate that calcitonin gene-related peptide (CGRP) is involved in neuropathic pain, this peptide being up-regulated in a small population of large- and medium-sized primary sensory neurons after peripheral nerve injury. In adult animals, the expression of CGRP is regulated by nerve growth factor (NGF). After nerve injury, NGF is up-regulated at the injury site for several weeks, and this up-regulation contributes to the onset of neuropathic pain. Using immunohistochemistry, we investigated the time course of the effect of an endoneurial injection of NGF on the expression of CGRP in primary sensory neurons. NGF increased the percentage of medium- to large-sized DRG neuron profiles expressing CGRP, did not modify the percentage of small-sized neurons expressing CGRP, and increased CGRP expression in the laminae III and IV of the dorsal horn. The effects of NGF were evident as soon as 1 day after endoneurial injection, and lasted for 5 days. Ten days after the injection of NGF, the patterns of CGRP expression in the DRG were normal, whereas a slight decrease in CGRP content was observed in the dorsal horn. The injection of vehicle did not produce any change on CGRP expression in primary sensory neurons. These results suggest that endoneurial NGF is responsible for the increase in CGRP expression in some large-sized neurons and their central processes observed after nerve injury in animal models of neuropathic pain. Our findings contribute to the understanding of the role of NGF in neuropathic pain.
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PMID:The effect of endoneurial nerve growth factor on calcitonin gene-related peptide expression in primary sensory neurons. 1582 52

In most parts of the peripheral nervous system galanin is expressed at very low levels. To further understand the functional role of galanin, a mouse overexpressing galanin under the platelet-derived growth factor-B was generated, and high levels of galanin expression were observed in several peripheral tissues and spinal cord. Thus, a large proportion of neurons in autonomic and sensory ganglia were galanin-positive, as were most spinal motor neurons. Strong galanin-like immunoreactivity was also seen in nerve terminals in the corresponding target tissues, including skin, blood vessels, sweat and salivary glands, motor end-plates and the gray matter of the spinal cord. In transgenic superior cervical ganglia around half of all neuron profiles expressed galanin mRNA but axotomy did not cause a further increase, even if mRNA levels were increased in individual neurons. In transgenic dorsal root ganglia galanin mRNA was detected in around two thirds of all neuron profiles, including large ones, and after axotomy the percentage of galanin neuron profiles was similar in overexpressing and wild type mice. Axotomy reduced the total number of DRG neurons less in overexpressing than in wild type mice, indicating a modest rescue effect. Aging by itself increased galanin expression in the superior cervical ganglion in wild type and transgenic mice, and in the latter also in preganglionic cholinergic neurons projecting to the superior cervical ganglion. Galanin overexpressing mice showed an attenuated plasma extravasation, an increased pain response in the formalin test, and changes in muscle physiology, but did not differ from wild type mice in sudomotor function. These findings suggest that overexpressed galanin in some tissues of these mice can be released and via a receptor-mediated action influence pathophysiological processes.
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PMID:Generation and phenotypic characterization of a galanin overexpressing mouse. 1589 31

The 29/30 amino acid neuropeptide galanin is present in a small population of DRG neurons under normal condition but is strongly upregulated after nerve injury. There is evidence that this upregulated galanin has trophic actions, for example promoting neurite outgrowth as well as influencing pain processing. In fact, both pro- and antinociceptive effects have been reported, probably relating to activation of different receptors. It has been proposed that presynaptic GalR2 receptors are pro-nociceptive by enhancing release of excitatory transmitters in the dorsal horn, and anti-nociceptive via an action on GalR1-positive interneurons. These neurons have recently been shown to be glutamatergic. Several other peptides and molecules are also regulated by nerve injury. Here we focus on neuropeptide tyrosine (NPY), which is upregulated in parallel with galanin. We review data reporting on coexistence between galanin and NPY and between these two peptides and the two NPY receptors Y1 and Y2. The data show considerable overlap, and it will be an important task to analyse how cross-talk between these neuropeptides can influence pain processing. It is proposed that such cross-talk can occur by release of peptides from DRGs neuron somata within dorsal root ganglia. To what extent these mechanisms shown to exist in rodents also occur in human is important, if one wants to discuss novel strategies for pain treatment on the basis of these findings. So far information is limited, but it has been demonstrated that galanin is expressed in DRGs and possibly also regulated.
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PMID:Galaninergic mechanisms at the spinal level: focus on histochemical phenotyping. 1589 17

Postoperative pain significantly impacts patient recovery. However, postoperative pain management remains suboptimal, perhaps because treatment strategies are based mainly on studies using inflammatory pain models. We used a recently developed mouse model of incisional pain to investigate peripheral and spinal mechanisms contributing to heat hyperalgesia after incision. Behavioral experiments involving TRPV1 KO mice demonstrate that, as previously observed in inflammatory models, TRPV1 is necessary for heat (but not mechanical) hyperalgesia after incision. However, in WT mice, neither the proportion of TRPV1 immunoreactive neurons in the DRG nor the intensity of TRPV1 staining in the sciatic nerve was different from that in controls up to 4 days after incision. This result was corroborated by immunoblot analysis of sciatic nerve in rats subjected to an incision, and is distinct from that following inflammation of the rat hind paw, a situation in which TRPV1 expression levels in sciatic nerve increases. In the absence of heat exposure, spinal c-Fos staining was similar between incised TRPV1 KO and WT mice. However, differences in c-Fos staining between heat exposed TRPV1 KO and WT mice after incision suggest that the incision-mediated enhancement of heat-evoked signaling to the spinal cord involves a TRPV1-dependent mechanism. Finally, heat hyperalgesia after incision was reversed by antagonism of spinal non-NMDA receptors, unlike inflammatory hyperalgesia, which is mediated via NMDA receptors . Thus, TRPV1 is important for the generation of thermal hyperalgesia after incision. Our observations suggest that all experimental pain models may not be equally appropriate to guide the development of postoperative pain therapies.
Pain 2005 Jun
PMID:Heat hyperalgesia after incision requires TRPV1 and is distinct from pure inflammatory pain. 1591 Nov 56

The epsilon isoform of protein kinase C (PKCepsilon) has emerged as a critical second messenger in sensitization toward mechanical stimulation in models of neuropathic (diabetes, alcoholism, and cancer therapy) as well as acute and chronic inflammatory pain. Signaling pathways leading to activation of PKCepsilon remain unknown. Recent results indicate signaling from cAMP to PKC. A mechanism connecting cAMP and PKC, two ubiquitous, commonly considered separate pathways, remains elusive. We found that, in cultured DRG neurons, signaling from cAMP to PKCepsilon is not mediated by PKA but by the recently identified cAMP-activated guanine exchange factor Epac. Epac, in turn, was upstream of phospholipase C (PLC) and PLD, both of which were necessary for translocation and activation of PKCepsilon. This signaling pathway was specific to isolectin B4-positive [IB4(+)] nociceptors. Also, in a behavioral model, cAMP produced mechanical hyperalgesia (tenderness) through Epac, PLC/PLD, and PKCepsilon. By delineating this signaling pathway, we provide a mechanism for cAMP-to-PKC signaling, give proof of principle that the mitogen-activated protein kinase pathway-activating protein Epac also stimulates PKC, describe the first physiological function unique for the IB4(+) subpopulation of sensory neurons, and find proof of principle that G-protein-coupled receptors can activate PKC not only through the G-proteins alpha(q) and betagamma but also through alpha(s).
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PMID:Epac mediates a cAMP-to-PKC signaling in inflammatory pain: an isolectin B4(+) neuron-specific mechanism. 1614 18

The P2X7 receptor is an ATP-sensitive ligand-gated cation channel, expressed predominantly in cells with immune origin. Recent studies have demonstrated that P2X7 may play an important role in pain signaling. In the present study, the expression of P2X7 receptors in non-neuronal cells and neurons isolated from dorsal root ganglia was characterized using patch clamp, pharmacological and confocal microscopy approaches. In small diameter DRG neurons, 100 microM 2', 3'-O-(4-benzoylbenzoyl)-ATP (BzATP) evoked an inward current, which was inhibited completely by 1 microM A-317491, a potent and selective P2X3 receptor antagonist. In contrast, BzATP evoked concentration-dependent increases in inward currents in non-neuronal DRG cells with an EC50 value of 26 +/- 0.14 microM, which were resistant to the blockade by A-317491. The activity to evoke cationic currents by P2X receptor agonists in non-neuronal cells showed a rank order of BzATP > ATP > alpha,beta-meATP. Pyridoxal-phosphate-6-azophenyl-,2',4'-disulphonic acid (PPADS) and Mg2+ produced concentration-dependent inhibition of BzATP-evoked currents in non-neuronal cells. Confocal microscopy revealed positive immunoreactivity of anti-P2X7 receptor antibodies on non-neuronal cells. No anti-P2X7 immunoreactivity was observed on DRG neurons. Further electrophysiological studies showed that prolonged agonist activation of P2X7 receptors in non-neuronal cells did not lead to cytolytic pore formation. Taken together, the present study demonstrated functional expression of P2X7 receptors in non-neuronal but not in small diameter neurons from rat DRG. Modulation of P2X7 receptors in non-neuronal cells might have impact on peripheral sensory transduction under normal and pathological states.
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PMID:Functional expression of P2X7 receptors in non-neuronal cells of rat dorsal root ganglia. 1600 56

The localization of the neuropeptide tyrosine (NPY) Y2 receptor (Y2R) protein was studied in mouse dorsal root ganglia (DRGs) and spinal cord, by using a recently developed rabbit anti-Y2R antibody and a sensitive immunohistochemical method. Y2R-like immunoreactivity (-LI) was observed in about 10% of the small/medium-sized lumbar DRG neurons. Among these, about 44% were calcitonin gene-related peptide-immunoreactive, and about 38% bound isolectin B4. In the dorsal horn of the spinal cord, an intense Y2R-LI was seen in the most superficial layers, mostly restricted to laminae I-II. This immunoreactivity was completely abolished by dorsal rhizotomy. Y2R-L1 was also detected on the skin, more abundantly in hairy than glabrous skin. Specificity experiments showed complete disappearance of the Y2R-LI described above after incubation with antibody preadsorbed with the immunogenic peptide. Furthermore, Y2R-LI was also absent in a Y2R knockout mouse. These results demonstrate that the NPY Y2R is associated mainly with both peptidergic and nonpeptidergic small, presumably nociceptive, neurons projecting to the superficial layers of the dorsal horn. The results also support a role for this receptor and NPY in pain mechanisms.
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PMID:Neuropeptide Y2 receptor protein is present in peptidergic and nonpeptidergic primary sensory neurons of the mouse. 1602 47

Recently, 1,3-diarylalkyl thioureas have merged as one of the promising nonvanilloid TRPV1 antagonists possessing excellent therapeutic potential in pain regulation. In this paper, the full structure-activity relationship for TRPV1 antagonism of a novel series of 1,3-diarylalky thioureas is reported. Exploration of the structure-activity relationship, by systemically modulating three essential pharmacophoric regions, led to six examples of 1,3-dibenzyl thioureas, which exhibit Ca(2+) uptake inhibition in rat DRG neuron with IC(50) between 10 and 100 nM.
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PMID:Novel potent antagonists of transient receptor potential channel, vanilloid subfamily member 1: structure-activity relationship of 1,3-diarylalkyl thioureas possessing new vanilloid equivalents. 1613 49


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