Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of Guangxin Dansheng Capsule on activating blood and eliminating stasis, regulating vital energy and alleviating pain were observed. The results showed that Guanxin Dansheng Capsule possessed obvious protective effects on acute cardiac muscle ischemia and could inhibit the aggregation of platelet induced by ADP, reduce the amount of oxygen consumed and prolong time of haemorrhage.
 ...
PMID:[Study on activating blood and eliminating stasis of guanxin dansheng capsule]. 1259 10

Membrane currents and changes in the intracellular Ca2+ concentration ([Ca2+]i) were measured in HEK293 cells transfected with the human P2X3 receptor (HEK293-hP2X3). RT-PCR and immunocytochemistry indicated the additional presence of endogenous P2Y1 and to some extent P2Y4 receptors. P2 receptor agonists induced inward currents in HEK293-hP2X3 cells with the rank order of potency alpha,beta-meATP approximately ATP > ADP-beta-S > UTP. A comparable rise in [Ca2+]i was observed after the slow superfusion of ATP, ADP-beta-S and UTP; alpha,beta-meATP was ineffective. These data, in conjunction with results obtained by using the P2 receptor antagonists TNP-ATP, PPADS and MRS2179 indicate that the current response to alpha,beta-meATP is due to P2X3 receptor activation, while the ATP-induced rise in [Ca2+]i is evoked by P2Y1 and P2Y4 receptor activation. TCE depressed the alpha,beta-meATP current in a manner compatible with a non-competitive antagonism. The ATP-induced increase of [Ca2+]i was much less sensitive to the inhibitory effect of TCE than the current response to alpha,beta-meATP. The present study indicates that in HEK293-hP2X3 cells, TCE, but not ethanol, potently inhibits ligand-gated P2X3 receptors and, in addition, moderately interferes with G protein-coupled P2Y1 and P2Y4 receptors. Such an effect may be relevant for the interruption of pain transmission in dorsal root ganglion neurons following ingestion of chloral hydrate or trichloroethylene.
 ...
PMID:Characterization of P2X3, P2Y1 and P2Y4 receptors in cultured HEK293-hP2X3 cells and their inhibition by ethanol and trichloroethanol. 1269 4

There is strong evidence for the presence of nucleotide (P2) receptors in sensory neurons, which might play a role in the transmission of pain signals. In contrast, virtually nothing is known about P2 receptors in satellite glial cells (SGCs), which are the main glial cells in sensory ganglia. We investigated the possibility that P2 receptors exist in SGCs in murine trigeminal ganglia, using Ca(2+) imaging, patch-clamp recordings, and immunohistochemistry. We found that ATP caused an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) in SGCs. As adenosine had no effect on [Ca(2+)](i), and the P2 receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid largely blocked the response to ATP we conclude that P1 receptors did not contribute to the responses. We obtained the following evidence that the responses to ATP were mediated by metabotropic P2Y receptors: (i) persistence of the responses in Ca(2+)-free solution, (ii) inhibition of the response by cyclopiazonic acid, (iii) [Ca(2+)](i) increases in response to the P2Y agonists uridine triphosphate, adenosine thiodiphosphate, and 2-methylthio ADP, and (iv) failure of the P2X agonist alpha,beta-methylene ATP to elicit a response. Agonists of P2Y(1) receptors and uridine triphosphate, an agonist at P2Y(2) and P2Y(4) receptors, induced [Ca(2+)](i) increases suggesting that at least these P2Y receptor subtypes are present on SGCs. Using an antibody against the P2Y(4) receptor, we found immunopositive SGCs. Patch-clamp recordings of SGCs did not reveal any inward current due to ATP. Therefore, there was no evidence for the activation of ionotropic P2X receptors under the present conditions. The results indicate the presence of functional nucleotide (P2Y) receptors in SGCs.
 ...
PMID:P2 receptors in satellite glial cells in trigeminal ganglia of mice. 1292 3

The ectonucleoside triphosphate diphosphohydrolases (NTPDases) control extracellular nucleotide concentrations, thereby modulating many important biological responses, including blood clotting and pain perception. NTPDases1-4 are oligomeric integral membrane proteins, whereas NTPDase5 (CD39L4) and NTPDase6 (CD39L2) are soluble monomeric enzymes, making them more amenable to thorough structural and functional analyses than the membrane-bound forms. Therefore, we report here the bacterial expression, refolding, purification, and biochemical characterization of the soluble portion of human NTPDase6. Consistent with the enzyme expressed in mammalian cells, this recombinant NTPDase6 efficiently hydrolyzes GDP, IDP, and UDP (specific activity of approximately 50000 micromol mg(-1) h(-1)), with slower hydrolysis of CDP, ITP, GTP, CTP, ADP, and UTP and virtually no hydrolysis of ATP. The K(m) for GDP (130 +/- 30 microM) is similar to that determined for the soluble rat NTPDase6 expressed in mammalian cells. The secondary structure of the refolded enzyme was determined by circular dichroism to be 33% alpha-helix, 18% beta-sheet, and 49% random coil, consistent with the secondary structure predicted from the amino acid sequence of soluble NTPDase6. Four of the five cysteine residues in the soluble NTPDase6 are highly conserved among all the NTPDases, while the fifth residue is not. Mutation of this nonconserved cysteine resulted in an enzyme very similar to wild type in its enzymology and secondary structure, indicating that this cysteine exists as a free sulfhydryl and is not essential for structure or function. The disulfide pairing of the other four cysteine residues was determined as Cys(249)-Cys(280) and Cys(340)-Cys(354) by HPLC and mass spectral analysis of tryptic peptides. Due to conservation of these cysteine residues, these two disulfide bonds are likely to exist in all NTPDases. A structural model for NTPDase6, incorporating these and other findings obtained with other NTPDases, is proposed.
 ...
PMID:Bacterial expression, characterization, and disulfide bond determination of soluble human NTPDase6 (CD39L2) nucleotidase: implications for structure and function. 1452 83

Like opioid tolerance, neuropathic pain syndrome manifested by hyperalgesia and allodynia responds poorly to opioids. Hitherto, its development is still not clear and its treatment and prevention are still disputable. Pertussis toxin (PTX) which ADP-ribosylates the alpha-subunit of inhibitory guanine nucleotide binding regulatory proteins (Gi/Go), is used to induce morphine tolerance through intrathecal (i.t.) injection. It decreases the antinociceptive effect of opioid receptor agonists, and produces a thermal hyperalgesia as well. With treatment of PTX the inhibitory Gi- and Go-proteins signal transduction is inactivated. Inhibition of the inhibitory system would likely lead to a predominance of the excitatory system. Intrathecal PTX administration has also been suggested as a model for study of the central mechanisms of neuropathic pain. In our previous studies, with intrathecal microdialysis and drug delivery techniques, we correlated the biochemical and pharmacological effects on the behavioral expressions of i.t. PTX-treated rats. Intrathecal PTX administration would induce thermal hyperalgesia in rats, with accompaniments of a prolonged increase in the concentrations of excitatory amino acids (EAAs), glutamate and aspartate, and a decrease in the concentration of the inhibitory amino acid (IAA) glycine in the spinal CSF dialysates. The PTX-induced thermal hyperalgesia peaked between day 2 and 4, but no cold allodynia is observed; i.t. administration of N-methyl-D-aspartate (NMDA) receptor antagonist, D-2-amino-5-phosponovaleric acid (D-AP5), glycine and protein kinase C (PKC) inhibitor chelerythrine attenuated the thermal hyperalgesia. The PKC gamma content of both synaptosomal and cytosolic fractions were significantly increased in PTX-treated rats. In contrast, the levels of PKC alpha, beta I, or beta II isozymes in these fractions were unaffected. Infusion of NMDA antagonist D-AP5 prevented both the thermal hyperalgesia and the increase in PKC gamma expression in PTX-treated rats. Similar to our previous report, i.t. PTX reduced morphine's analgesic effect. PKC inhibitor chelerythrine attenuated this reduction of morphine's analgesia, and an inhibition of the morphine-evoked EAAs release was observed in PTX-treated rats as well. Taken together, i.t. PTX-induced neuropathic pain syndrome is accompanied by increasing of EAAs, decreasing of IAA release, and a selective increasing of PKC gamma expression in the spinal cord. Inhibition of PKC not only blocked thermal hyperalgesia, but also reversed the reduction of morphine's analgesic effect in PTX-rats. These results suggest that PTX-induced neuropathic pain syndromes are involved in EAAs, IAAs and PKC alternations.
 ...
PMID:Implications of intrathecal pertussis toxin animal model on the cellular mechanisms of neuropathic pain syndrome. 1476 16

1. Fast-desensitizing P2X(3) receptors of nociceptive dorsol root ganglion (DRG) neurons are thought to mediate pain sensation. Since P2X(3) receptor efficiency is powerfully modulated by desensitization, its underlying properties were studied with patch-clamp recording. 2. On rat cultured DRG neurons, 2 s application of ATP (EC(50)=1.52 microm), ADP (EC(50)=1.1 microm) or alpha,beta-meATP (EC(50)=1.78 microm) produced similar inward currents that fully desensitized, at the same rate, back to baseline. Recovery from desensitization was much slower after ATP and ADP than after alpha,beta-meATP and, in all cases, it had sigmoidal time course. 3. By alternating the application of ATP and alpha,beta-meATP, we observed complete cross-desensitization indicating that these agonists activated the same receptors. This notion was confirmed by the similar antagonism induced by 2', 3'-O-(2,4,6,trinitrophenyl)-adenosine triphosphate (TNP-ATP). 4. Recovery from desensitization elicited by ATP was unexpectedly shaped by transient application of alpha,beta-methylene-adenosine triphosphate (alpha,beta-meATP), and vice versa. Thus, short-lasting, full desensitization produced by alpha,beta-meATP protected receptors from long-lasting desensitization induced by subsequent ATP applications. ATP and ADP had similar properties of recovery from desensitization. 5. Low nm concentrations of alpha,beta-meATP (unable to evoke membrane currents) could speed up recovery from ATP-induced desensitization, while low nm concentrations of ATP enhanced it. Ambient ATP levels were found to be in the pm range (52+/-3 pm). 6. The phenomenon of cross-desensitization and protection was reproduced by rP2X(3) receptors expressed by rat osteoblastic cell 17/2.8 or human embryonic kidney cell 293 cells, indicating P2X(3) receptor specificity. 7. It is suggested that transient application of an agonist that generates rapid recovery from desensitization, is a novel, powerful tool to modulate P2X(3) receptor responsiveness to the natural agonist ATP.
 ...
PMID:Agonist-dependence of recovery from desensitization of P2X(3) receptors provides a novel and sensitive approach for their rapid up or downregulation. 1498 Sep 81

Pathological pain is often associated with changed sympathetic nerve activities. It is known that sympathetic nerve endings release ATP as a co-transmitter of norepinephrine, but the effect of this ATP on the nociceptive system has not been properly studied in that the concentration range used in the previous studies was much higher than is expected in the surroundings of nociceptor terminals. We examined the effects of ATP, especially at low concentration (10(-5) M or less), on C-fiber polymodal receptor (CPR) activity using a rat skin-nerve preparation in vitro. We found for the first time that ATP inhibited the heat response of CPRs at low concentration (10(-5) M), but facilitated it at high concentration (10(-3) M). The former effect was mimicked by a P2X3 agonist, alpha,beta-methylene ATP, at 10(-5) M, while the latter was mimicked by 2-methylthio ADP (a P2Y1 agonist) or UTP (a P2Y2 agonist) at 10(-3) M, suggesting that the former is mediated by P2X receptors and the latter by P2Y receptors. After repetitive heat stimuli, ATP-induced CPR excitation was increased (10(-5) to 10(-3) M), but none of the purinergic agonists induced CPR excitation in a magnitude comparable to that by ATP. Possible mechanisms for these effects were discussed.
 ...
PMID:Inhibitory, facilitatory, and excitatory effects of ATP and purinergic receptor agonists on the activity of rat cutaneous nociceptors in vitro. 1574 Aug 3

The release of nucleotides in extracellular fluids can result from cell necrosis, exocytosis of secretory granules (such as platelet dense granules), or efflux through membrane channels. In addition, recent evidence suggests that vesicular trafficking is an important pathway of nucleotide release. Once in the extracellular fluids, they are rapidly degraded by ectonucleotidases, such as CD39, that play a key role in neutralizing the platelet aggregatory action of adenosine diphosphate (ADP), and act on two families of receptors: the ionotropic P2X receptors and the G-protein-coupled P2Y receptors. The family of P2X receptors encompasses seven genes. Currently, there are eight genuine P2Y receptors that can be subdivided into two structurally distinct subfamilies. Whereas P2X receptors are receptors of ATP, the different P2Y receptors are activated by distinct nucleotides, diphosphates or triphosphates, or purines or pyrimidines, some of them being conjugated to sugars. The study of knockout mice has demonstrated that P2X receptors play important roles in the neurogenic control of smooth muscle contraction, in pain and visceral perception, and in macrophage functions. The phenotype of P2Y null mice so far is more restricted: inhibition of platelet aggregation to ADP and increased bleeding time in P2Y (1)(-/-) and P2Y (12)(-/-) mice and lack of epithelial responsiveness to nucleotides in airways (P2Y (2)(-/-)) and intestine (P2Y (4)(0/-)).
 ...
PMID:Overview of the P2 receptors. 1585 17

Improvement of endothelial function caused by statin treatment is not related to lowering of the cholesterol levels but results primarily from statin pleiotropic effects. Accordingly, we designed a pilot study in 10 normocholesterolaemic and 10 hypercholesterolaemic patients with peripheral arterial occlusive disease to investigate potential biological effects of statins in relation to their effects on endothelial function. The patients were treated with simvastatin 40 mg/daily for 3 months. Simvastatin led to significant reduction in total cholesterol and trigliceride levels in normocholesterolaemic and hypercholesterolaemic patients. Elongation of pain-free and total walking distance was observed in both groups studied. Inconsiderable changes in rest ankle brachial index were seen. Flow-mediated dilation increased in normocholesterolaemic group by 153% and in the hypercholesterolaemic group by 180% after 3 months of treatment. Euglobulin clot lysis time was shortened significantly in both groups each time after drug intake. Platelet aggregates ratio was increased in normocholesterolaemic patients by 8.9% and in hypercholesterolaemic patients by 17.6% each time after intake and remained significantly increased during the observation after 1 and 3 months. Simvastatin inhibited platelet aggregation induced by collagen and ADP in both study groups 3 hr after intake, but the platelets of hypercholesterolaemic patients were less sensitive to these aggregatory agents after 3 months of treatment. Simvastatin therapy caused clinical improvement in normocholesterolaemic and hypercholesterolaemic patients with peripheral occlusive disease. It is suggested that this effect is due to the restoration of endothelial function.
 ...
PMID:Simvastatin effects in normo- and hypercholesterolaemic patients with peripheral arterial occlusive disease: a pilot study. 1591 Apr 4

1. Extracellular ATP is recognized as a peripheral modulator of pain. Activation of ionotropic P2X receptors in sensory neurons has been implicated in induction of pain, whereas metabotropic P2Y receptors in potentiation of pain induced by chemical or physical stimuli via capsaicin sensitive TRPV1 channel. Here we report that P2Y2 receptor activation by ATP can activate the TRPV1 channel in absence of any other stimuli. 2. ATP-induced Ca2+ signaling was studied in Neuro2a cells. ATP evoked release of intracellular Ca2+ from ER and Ca2+ influx through a fast inactivating channel. The Ca2+ response was induced by P2Y receptor agonists in the order of potency ATP>or=UTP>or=ATPgammaS>ADP and was inhibited by suramin and PPADS. The P2X receptor agonist alpha beta methyl ATP was ineffective. 3. The Ca2+ influx was blocked by ruthenium red, an inhibitor of TRPV1 channel. Capsaicin, the most potent activator of the TRPV1 channel, evoked a fast inactivating Ca2+ transient suggesting the presence of endogenous TRPV1 channels in Neuro2a cells. NMS and PDBu, repressors of IP3 formation, drastically inhibited both the components of Ca2+ response. 4. Our data show co-activation of the P2Y2 receptor and capsaicin sensitive TRPV1 channel by ATP. Such functional interaction between endogenous P2Y2 receptor and TRPV1 channels could explain the ATP-induced pain.
 ...
PMID:Co-activation of P2Y2 receptor and TRPV channel by ATP: implications for ATP induced pain. 1613 36


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>