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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Physiological pain is an essential experience that alerts us to the presence of external or internal stimuli that are damaging or are potentially tissue-damaging. By contrast, pathological pain is not tied to the presence of tissue-damaging stimuli. One type of pathological pain-neuropathic pain--is often a consequence of nerve injury or of diseases such as diabetes, HIV AIDS or cancer, that damage peripheral nerves. Neuropathic pain can be agonizing, persistent over long periods, and, unfortunately, is often resistant to known pain-killers. Recent advances in our understanding of the mechanisms producing neuropathic pain have been made by defining causal roles of spinal microglia in the pathogenesis of neuropathic pain as several molecules including P2X4 receptors, which are present in activated microglia, have been found to be required molecular mediators. We expect that understanding the key roles of these molecules in spinal microglia may lead to new strategies for the management of neuropathic pain, strategies not previously anticipated by a neuron-centric view of pain plasticity in the dorsal horn.
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PMID:[Role of molecules expressed in spiral microglia in neuropathic pain]. 1663 97

Emerging evidence indicates that microglia play a critical role in the pathogenesis of neuropathic pain, a debilitating chronic pain condition that can occur after peripheral nerve damage caused by disease, infection, or physical injury. Microglia are immunocompetent cells of the central nervous system and express various ionotropic P2X and metabotropic P2Y purinoceptors. After injury to a peripheral nerve, microglia in the spinal cord become activated and upregulate expression of the P2X4 receptor. Recent findings suggest that activation of P2X4 receptors evokes release of brain-derived neurotrophic factor from microglia and that this mediates microglia-neuron signaling leading to pain hypersensitivity. Thus, P2X4 receptors and the intracellular signaling mediators in microglia are promising therapeutic targets for the development of novel pharmacological agents in the management of neuropathic pain.
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PMID:Purinoceptors in microglia and neuropathic pain. 1676 66

Microglia, activated when physiological homeostasis is threatened, play an important role as immune cells in the CNS. Activated microglia show a progressive series of changes in morphology, gene expression, function and number, and produce and release various chemical mediators, including proinflammatory cytokines that can produce immunological actions and modify neuronal function. Recently, accumulating evidence has indicated an important role for ATP receptors of activated microglia in neuropathic pain. Neuropathic pain is often a consequence of nerve injury through surgery, bone compression, cancer, diabetes or infection. The expression of the P2X4 receptor, a subtype of ATP receptors, is enhanced in spinal microglia in a peripheral nerve injury model, and blocking pharmacologically and suppressing molecularly P2X4 receptors produces a reduction of the neuropathic pain. Several cytokines such as interleukin 6 (IL6) and tumour necrosis factor alpha (TNFalpha) in the dorsal horn are also increased after nerve lesion and have been implicated in contributing to nerve-injury pain. ATP can activate mitogen-activated protein kinase (MAPK) leading to the release of bioactive substances including cytokines from microglia. Thus, diffusible factors released from activated microglia by the stimulation of purinergic receptors may have an important role in the development of neuropathic pain.
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PMID:ATP receptors of microglia involved in pain. 1680 36

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

Neuropathic pain is often a consequence of nerve injury through surgery, bone compression, diabetes or infection. This type of pain can be so severe that even light touching can be intensely painful. Unfortunately, this state is generally resistant to currently available treatments. There is abundant evidence that activated microglia are a key player for causing the pain and ATP receptors expressed in microglia have an important role to activate microglia. In this review, we summarize the role of microglia and ATP receptors in neuropathic pain signalling. The activated microglia express P2X4 after nerve injury, which can be stimulated by endogenous ATP, resulting in the release of BDNF which is one of key molecules involving in neuropathic pain. The microglia also express many molecules that were reported to be connected in the pain. Understanding the key roles of these ATP receptors in microglia may lead to new strategies for the management of intractable chronic pain.
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PMID:[Involvement of microglia in neuropathic pain signalling]. 1766 45

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

P2X receptors (P2XRs) are trimeric ATP-gated cation channels. Seven subunits have been cloned. P2X4 and P2X7 subunits show overlapping expression and both subunits are involved in pathophysiological processes such as inflammatory and neuropathic pain. A recent study provides evidence for heteromeric P2X4/7Rs. In this study, subtype-specific antibodies in combination with BN-PAGE are used to directly visualize P2XR complexes solubilized from membrane extracts of native tissues. The results show specific P2X7R and P2X4R staining in many tissues. The P2X7 complex has a clearly different size than the P2X4 complex but is likewise composed of three subunits. No complexes corresponding to more than three subunits could be detected. Also, no complexes of intermediate size or reactive to both antibodies were detected. These data suggest that either heteromerization between P2X4 and P2X7 subunits results not in stable heteromeric complexes or P2X4/7 heteromers do not represent a dominant subtype in the tissues investigated.
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PMID:Homotrimeric complexes are the dominant assembly state of native P2X7 subunits. 1893 36


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