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)

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

Adenosine and ATP, via P1 and P2 receptors respectively, can modulate pain transmission under physiological, inflammatory, and neuropathic pain conditions. Such influences reflect peripheral and central actions and effects on neurons as well as other cell types. In general, adenosine A1 receptors produce inhibitory effects on pain in a number of preclinical models and are a focus of attention. In humans, i.v. infusions of adenosine reduce some aspects of neuropathic pain and can reduce postoperative pain. For P2X receptors, there is a significant body of information indicating that inhibition of P2X3 receptors may be useful for relieving inflammatory and neuropathic pain. More recently, data have begun to emerge implicating P2X4, P2X7 and P2Y receptors in aspects of pain transmission. Both P1 and P2 receptors may represent novel targets for pain relief.
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PMID:Adenosine and ATP receptors. 1708 28

Growing evidence supports a role for the immune system in the induction and maintenance of chronic pain. ATP is a key neurotransmitter in this process. Recent studies demonstrate that the glial ATP receptor, P2X7, contributes to the modulation of pathological pain. To further delineate the endogenous mechanisms that are involved in P2X7-related antinociception, we utilized a selective P2X7 receptor antagonist, A-438079, in a series of in vivo and in vitro experiments. Injection of A-438079 (10-300 micromol/kg, i.p.) was anti-allodynic in three different rat models of neuropathic pain and it attenuated formalin-induced nocifensive behaviors. Using in vivo electrophysiology, A-438079 (80 micromol/kg, i.v.) reduced noxious and innocuous evoked activity of different classes of spinal neurons (low threshold, nociceptive specific, wide dynamic range) in neuropathic rats. The effects of A-438079 on evoked firing were diminished or absent in sham rats. Spontaneous activity of all classes of spinal neurons was also significantly reduced by A-438079 in neuropathic but not sham rats. In vitro, A-438079 (1 microM) blocked agonist-induced (2,3-O-(4-benzoylbenzoyl)-ATP, 30 microM) current in non-neuronal cells taken from the vicinity of the dorsal root ganglia. Furthermore, A-438079 dose-dependently (0.3-3 microM) decreased the quantity of the cytokine, interleukin-1beta, released from peripheral macrophages. Thus, ATP, acting through the P2X7 receptor, exerts a wide-ranging influence on spinal neuronal activity following a chronic injury. Antagonism of the P2X7 receptor can in turn modulate central sensitization and produce antinociception in animal models of pathological pain. These effects are likely mediated through immuno-neural interactions that affect the release of endogenous cytokines.
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PMID:P2X7-related modulation of pathological nociception in rats. 1747 48

The ionotropic P2X7 receptor (P2X7R) has become the focus of intense research interest for a number of reasons: i) it is a cation selective ion channel that is modulated by extracellular ATP. Upon stimulation by high concentrations of ATP it generates a non-selective membrane pore which is permeable to hydrophilic molecules with molecular weight up to 900 Da. ii) Though its physiological function is yet to be fully understood, there is high P2X7R expression in microglia. Importantly, this implies a pivotal role for the P2X7R in neuro-inflammatory and -degenerative processes. In addition, P2X7R-stimulated release of traditional neurotransmitters in the brain, such as glutamate and GABA, further supports the involvement of P2X7R in neuro-inflammatory and -degenerative processes. P2X7-knockout animals are also found to be resistant to inflammation and neuropathic pain, which suggests that P2X7 antagonists could potentially serve as all-purpose analgesics. Recent advances in the development of P2X7R ligands have resulted in identification of several different classes of P2X7R antagonists, including ATP analogues (oxidized ATP), dyes (Brilliant Blue G), tyrosine derivatives (KN-62 and KN-04), cyclic imides, adamantane and benzamide derivatives. A KN-62 related radioligand has also recently been reported for use in receptor binding assays. A more extensive range of potent, selective P2X7R ligands is required for a better understanding of the cascade of cellular processes associated with the P2X7R. This article will review P2X7R ligands discovered to date, together with their biological activity and therapeutic potential.
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PMID:Molecular probes for P2X7 receptor studies. 1758 60

Activation of microglia has been implicated in many neurological conditions including Alzheimer's disease and neuropathic pain. Recent studies provide evidence that P2X ATP receptors on the surface of microglia play a crucial role in initiation of inflammatory cascades. We investigated changes in surface P2X receptors in BV-2 murine microglial cells following their activation by pro-inflammatory bacterial lipopolysaccharides (LPS). mRNA analysis using RT-PCR confirmed the presence of P2X4 and P2X7 as the main P2X subunits. Application of ATP at low (< or =100 microM) and high (> or =1 mM) concentrations, as well as BzATP, activated inward currents in BV-2 cells. Current responses of P2X4 and P2X7 subtypes could be distinguished based on their respective sensitivity to the positive modulator ivermectin and to the antagonist Brilliant Blue G. Treatment of BV-2 cells with LPS leads to a transient increase in ivermectin-sensitive P2X4 currents, while dominant P2X7 currents remain largely unaffected. This increase in P2X4 function was concomitant with higher receptor protein expression, itself related to an upregulation of P2X4 mRNA levels that peaked at 48 h post-LPS treatment. Our data demonstrate that although LPS activation has a minor impact on P2X7 receptors that remain the major ionotropic ATP receptors in microglia, it specifically enhances responses to low ATP concentrations mediated by P2X4 receptors, highlighting the significant contribution of both subtypes to neuroinflammatory mechanisms and pathologies.
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PMID:Differential regulation of microglial P2X4 and P2X7 ATP receptors following LPS-induced activation. 1767 90

The cytolytic ionotropic ATP receptor P2X7 has several important roles in immune cell regulation, such as cytokine release, apoptosis, and microbial killing. Although P2X7 receptors are frequently coexpressed with another subtype of P2X receptor, P2X4, they are believed not to form heteromeric assemblies but to function only as homomers. Both receptors play a role in neuropathic pain; therefore, understanding how they coordinate the cellular response to ATP is important for the development of effective pain therapies. Here, we provide biochemical and electrophysiological evidence for an association between P2X4 and P2X7 that increases the diversity of receptor currents mediated via these two subtypes. The heterologously expressed receptors were coimmunoprecipitated from human embryonic kidney (HEK) 293 cells, and the endogenous P2X4 and P2X7 receptors were similarly coimmunoprecipitated from bone marrow-derived macrophages. In HEK293 cells, the fraction of P2X4 receptors biotinylated at the plasma membrane increased 2-fold in the presence of P2X7 although there was no change in overall expression. Coexpression of a dominant-negative P2X4 mutant (C353W) with P2X7, inhibited P2X7 receptor mediated currents by greater than 2-fold, whereas a nonfunctional but non-dominant-negative mutant (S341W) did not. Coexpression of P2X4S341W with P2X7 produced a current that was potentiated by ivermectin and inhibited by 2',3'-O-(2,4,6-trinitrophenyl) adenosine 5-triphosphate (TNP-ATP), whereas expression of P2X7 alone produced a current that was insensitive to both of these compounds at the concentrations used. These results demonstrate a structural and functional interaction between P2X4 and P2X7, which suggests that they associate to form heteromeric receptors.
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PMID:Evidence for functional P2X4/P2X7 heteromeric receptors. 1789 6

Neuropathic pain resulting from nerve injury or from diseases such as diabetes, HIV AIDS or cancer, that damage the peripheral nerves, can be agonizing, persistent over long periods, and, unfortunately, is often resistant to known pain-killers. The P2X receptors, of which seven subtypes (P2X1-P2X7) have been cloned, are a family of ligand-gated cation channels activated by extracellular ATP and have important roles in regulating neuronal and glial functions in the nervous system. Recent advances in our understanding of the mechanisms underlying neuropathic pain have been made by defining important roles of P2X4 receptors and spinal microglia in the pathogenesis of neuropathic pain. Within the spinal dorsal horn, peripheral nerve injury leads to a progressive series of changes in microglia including morphological hypertrophy of the cell body and proliferation that are considered indicative of activation. Furthermore, P2X4 receptors that which are upregulated in activated microglia, have been found to be essential molecular mediators. The activation of P2X4 receptors releases brain-derived neurotrophic factor from microglia; this mediates the signaling from microglia to neurons, which in turn leads to pain hypersensitivity. We expect that understanding the key roles of these molecules in spinal microglia may lead to new strategies for the management of neuropathic pain.
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PMID:[Neuropathic pain and ATP receptors in spinal microglia]. 1788 77

P2X receptors (P2XR) function as ATP-gated nonselective ion channels permeable to Na+, K+, and Ca2+, and they are expressed in a wide range of excitable, epithelial/endothelial, and immune effector cell types. The channels are trimeric complexes composed of protein subunits encoded by seven different P2XR genes expressed in mammalian and other vertebrate genomes. Current genetic, biochemical, and/or physiological evidence indicates that the extended family of functional P2X receptors includes six homomeric channels composed of P2X1, P2X2, P2X3, P2X4, P2X5, or P2X7 subunits and six heteromeric channels that involve subunit pairings of P2X1/P2X2, P2X1/P2X4, P2X1/P2X5, P2X2/P2X3, P2X2/P2X6, or P2X4/P2X6. Thus, all P2XR subtypes--with the salient exception of P2X7R--have previously been implicated in the assembly of heteromeric ATP-gated ion channels that can comprise unique pharmacological targets in different tissues. The assumed "go-it alone" function of the P2X7R has important implications because agents that target this particular receptor have been proposed as useful therapeutics in various autoinflammatory diseases or amelioration of inflammatory pain. However, this assumption and the interpretations based on it now require reevaluation in light of a new report in this issue of Molecular Pharmacology (p. 1447) that provides convincing biochemical and electrophysiological evidence for the existence of P2X4/P2X7 heteromeric receptors.
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PMID:Go it alone no more--P2X7 joins the society of heteromeric ATP-gated receptor channels. 1778 80

Some inflammatory mediators play an important role not only in the pathogenesis of the inflammatory pain, but also in that of neuropathic and visceral pain. We previously showed the antihyperalgesic effect of oATP, the inhibitor of the P2X7 receptors for the pro-nociceptive ATP, in experimental inflammation. Here we show the antihyperalgesic effect of oATP in mouse models of neuropathic and visceral pain, other than in a model of arthritic pain mimicking rheumatoid arthritis in humans. We also show that mice lacking P2X7 receptors (KO) are resistant to hyperalgesic thermal stimuli following the induction of arthritic, neuropathic and visceral pain. Local (injection into the right hind paw) pre-treatment with oATP is able to prevent the successive induction of ATP-dependent hyperalgesia in wild type mice. In addition, KO mice are not insensitive to intraplantar treatment with ATP. Our data suggest that, even if oATP is able to inhibit purinoceptors different from P2X7, the latter are the more important involved in pain transmission.
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PMID:Periodate oxidized ATP (oATP) reduces hyperalgesia in mice: involvement of P2X7 receptors and implications for therapy. 1833 32

N'-aryl acyl hydrazides were identified as P2X7 receptor antagonists. Structure-activity relationship (SAR) studies evaluated functional activity by monitoring calcium flux inhibition in cell lines expressing recombinant human and rat P2X7 receptors. Selected analogs were assayed in vitro for their capacity to inhibit release of cytokine IL-1beta. Compounds with potent antagonist function were evaluated in vivo using the zymosan-induced peritonitis model. A representative compound effectively attenuated mechanical allodynia in a rat model of neuropathic pain.
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PMID:Structure-activity relationship studies on N'-aryl carbohydrazide P2X7 antagonists. 1843 86


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