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)

ATP receptors in the central nervous system (CNS) are divided into 2 major classes, ionotropic (P2Xn) and G protein-coupled (P2Yn) ATP receptors. P2Xn receptors, a member of the 2-transmembrane family, contain non-selective cation channels that may play a role in rapid synaptic transmission. Seven subtypes of P2Xn were reported so far. Although all of these subtypes are distributed in the CNS, P2X4 and P2X6 are most abundantly and widely distributed. P2X3 is distributed only in trigeminal ganglia neurons as well as in small-diameter DRG neurons, suggesting their relation to pain. P2Yn receptors, a member of the 7-transmembrane superfamily, are coupled with Gq/11 to activate PLC beta. These receptors are thought to play an important role in the modulation of synaptic efficacy. Seven subtypes of P2Yn were reported so far. P2Y1, P2Y2, P2Y3 and P2Y4 are distributed in the CNS. Neither selective agonists nor antagonists to P2Xn and P2Yn are known.
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PMID:[ATP receptors in the central nervous system]. 939 22

P2X receptors are a family of ligand-gated ion channels responsive to ATP. Seven subtypes have been identified which form homo-multimeric or hetero-multimeric pores. P2X3 receptors are selectively expressed predominantly on small-diameter nociceptive sensory neurones in the dorsal root, trigeminal and nodose ganglia, particularly the non-peptidergic subpopulations labelled with the lectin IB4. P2X2/3 labelling is also present in inner lamina II of the spinal cord and in sensory nerve projections to skin and viscera, but few receptors are present in skeletal muscle. P2X3 receptors are down-regulated after peripheral nerve injury and their expression can be regulated by glial cell-derived neurotrophic factor. P2X receptor activation of sensory neurones has been demonstrated in in vivo pain models, including the rat hindpaw and knee-joint preparations, as well as in inflammatory models. P2X4 and/or P2X6 receptors in the CNS also seem to be involved in pain pathways. Non-nociceptive P2 receptors on sensory nerves are present in muscle and on sensory endings in the heart and lung that initiate reflex activity involving vagal afferent and efferent nerve fibres. The sources of ATP involved in nociception and non-nociceptive sensory nerve stimulation are discussed as well as a novel hypothesis about purinergic mechanosensory transduction.
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PMID:P2X receptors in sensory neurones. 1082 99

We have studied the modulatory effect of dehydroepiandrosterone (DHEA), the most abundant neurosteroid produced by glial cells and neurones, on membrane currents induced by the activation of ionotropic ATP (P2X) receptors in neonatal rat dorsal root ganglion neurones. ATP (1 microM) induced three types of currents/responses termed F (fast and transient), S (slowly desensitizing) and M (mixed, sum of F- and S-type responses). DHEA (10 nM to 100 microM) concentration-dependently increased the amplitude of plateau-like currents of S- and M-type responses evoked by submaximal (1 microM) but not saturating (100 microM or 1 mM) concentrations of ATP. Alphabeta-methylene ATP (alphabetame-ATP, 5 microM) also evoked F-, S- and M-type responses, the plateau phases of which were potentiated by lowering external pH (6.3) and by ivermectin (IVM, 3 microM), indicating the presence heteromeric P2X2-containing receptors and possibly of functional native P2X4/6 receptors. There was a strict correlation between the potentiating effects of low pH and DHEA on alphabetame-ATP responses but not between that of IVM and DHEA, suggesting that DHEA selectively modulated P2X2-containing receptors. DHEA also potentiated putative homomeric P2X2 receptor responses recorded in the continuous presence of 1 microM 2'-(or 3')-O-(2,4,6-trinitrophenyl) adenosine 5'-triphosphate (TNP-ATP). Our results constitute the first demonstration of a fast potentiation of P2X receptors by a neurosteroid and suggest that DHEA could be an endogenous modulator of P2X2-containing receptors thereby contributing to the facilitation of the detection and/or the transmission of nociceptive messages, particularly under conditions of inflammatory pain where the P2X receptor signalling pathway appears to be upregulated.
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PMID:Dehydroepiandrosterone potentiates native ionotropic ATP receptors containing the P2X2 subunit in rat sensory neurones. 1284 12

Pain after nerve damage is an expression of pathological operation of the nervous system, one hallmark of which is tactile allodynia-pain hypersensitivity evoked by innocuous stimuli. Effective therapy for this pain is lacking, and the underlying mechanisms are poorly understood. Here we report that pharmacological blockade of spinal P2X4 receptors (P2X4Rs), a subtype of ionotropic ATP receptor, reversed tactile allodynia caused by peripheral nerve injury without affecting acute pain behaviours in naive animals. After nerve injury, P2X4R expression increased strikingly in the ipsilateral spinal cord, and P2X4Rs were induced in hyperactive microglia but not in neurons or astrocytes. Intraspinal administration of P2X4R antisense oligodeoxynucleotide decreased the induction of P2X4Rs and suppressed tactile allodynia after nerve injury. Conversely, intraspinal administration of microglia in which P2X4Rs had been induced and stimulated, produced tactile allodynia in naive rats. Taken together, our results demonstrate that activation of P2X4Rs in hyperactive microglia is necessary for tactile allodynia after nerve injury and is sufficient to produce tactile allodynia in normal animals. Thus, blocking P2X4Rs in microglia might be a new therapeutic strategy for pain induced by nerve injury.
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PMID:P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. 1291 63

Pain following nerve damage is an expression of pathological operation of the nervous system, one hallmark of which is tactile allodynia. We have been studying the role of ATP receptors in pain, and have already reported that activation of the P2X2/3 heteromeric channel/receptor in primary sensory neurons causes acutely tactile allodynia. We report here that tactile allodynia under chronic pain states requires an activation of the P2X4 ionotropic ATP receptor and p38 mitogen-activated protein kinase (MAPK) in spinal cord microglia. Two weeks after L5 spinal nerve injury, rats displayed a marked mechanical allodynia. In the rats, activated microglia were detected in the injury side of the dorsal horn where the level of the dually phosphorylated active form of p38MAPK (phospho-p38MAPK) was increased. We performed the double-immunostaining analysis using cell-type specific markers and found that phospho-p38MAPK-positive cells were microglia. Moreover, intraspinal administration of p38MAPK inhibitor, SB203580, suppressed the allodynia. We also found that the expression level of P2X4 was increased strikingly in spinal cord microgila after nerve injury and that pharmacological blockade of P2X4 reversed the allodynia. Intraspinal administration of P2X4 antisense oligodeoxynucleotide (ODN) reduced induction of P2X4 and suppressed tactile allodynia. Taken together our results demonstrate that activation of P2X4 or p38 MAPK in spinal cord microglia is necessary for tactile allodynia following nerve injury.
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PMID:Chronic pain and microglia: the role of ATP. 1546 44

P2X4 receptor (P2X4R) is an ion channel gated by adenosine 5'-triphosphate. Here we report the presence and the distribution of P2X4R in rat spinal cord by immunohistochemical analysis in an inflammatory pain model. Peripheral inflammation was induced by subcutaneous injection of 4% formalin into the rat hindpaw. Morphology, spatial localization, and activation state of P2X4R+ cells were described at 1, 5, 7, 14, and 28 days after injury. In normal and saline treated control rats, P2X4R was rarely seen. After formalin administration, an increase of P2X4R+ microglia were observed in the spinal cord dorsal horn on the side ipsilateral to the injection, reaching maximal levels by day 7, and then decreasing to normal levels by day 14. This implicates a role of P2X4R in the spinal inflammatory pain process. Furthermore, formalin-induced region-specific increase in activated microglia was confirmed by ED1 and endothelial monocytes activating polypeptide II (EMAP-II) expression. In conclusion, this is the first demonstration that P2X4R is expressed by microglia in the inflammatory pain.
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PMID:Expression of P2X4 receptor by lesional activated microglia during formalin-induced inflammatory pain. 1588 14

Following spinal cord injury (SCI), neuropathic, chronic pain is a major cause of disability. Recently, glial P2X4 receptor (P2X4R) has been identified as a major contributor to the development of neuropathic pain after peripheral nerve injury. Here we report analysis of P2X4R expression following rat SCI. Significant lesional accumulation of P2X4R+ cells was detected as early as 24 h after SCI, reaching maximum cell numbers on Day 7. Thereafter cell numbers declined but persisted at significantly elevated, sub-maximal levels (>70%) until 1 month post injury. Double-immunolabeling identified the majority of lesional P2X4R+ cells as activated microglia/macrophages and surviving neurons/neurites. Increase of P2X4R+, beta-APP+ hypertrophic neurites correlated with proximity to the lesion. Further, P2X4R+ cells coexpressed the intracellular regulators of signalling cascades, COX-1 (>20%), COX-2 (>5%), RhoA (>60%) and RhoB (>10%).
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PMID:Spinal cord injury induces early and persistent lesional P2X4 receptor expression. 1588 21

Microglia play an important role as immune cells in the central nervous system (CNS). Microglia are activated in threatened physiological homeostasis, including CNS trauma, apoptosis, ischemia, inflammation, and infection. Activated microglia show a stereotypic, 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 can also act on neurons to alter their function. Recently, a great deal of attention is focusing on the relation between activated microglia through adenosine 5'-triphosphate (ATP) receptors and neuropathic pain. 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 and it is generally resistant to currently available treatments. There is abundant evidence that extracellular ATP and microglia have an important role in neuropathic pain. The expression of P2X4 receptor, a subtype of ATP receptors, is enhanced in spinal microglia after peripheral nerve injury model, and blocking pharmacologically and suppressing molecularly P2X4 receptors produce a reduction of the neuropathic pain. Several cytokines such as interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) in the dorsal horn are increased after nerve lesion and have been implicated in contributing to nerve-injury pain, presumably by altering synaptic transmission in the CNS, including the spinal cord. Nerve injury also leads to persistent activation of p38 mitogen-activated protein kinase (MAPK) in microglia. An inhibitor of this enzyme reverses mechanical allodynia following spinal nerve ligation (SNL). ATP is able to activate 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. Understanding the key roles of ATP receptors, including P2X4 receptors, in the microglia may lead to new strategies for the management of neuropathic pain.
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PMID:The function of microglia through purinergic receptors: neuropathic pain and cytokine release. 1616 95

Following hints in the early literature about adenosine 5'-triphosphate (ATP) injections producing pain, an ion-channel nucleotide receptor was cloned in 1995, P2X3 subtype, which was shown to be localized predominantly on small nociceptive sensory nerves. Since then, there has been an increasing number of papers exploring the role of P2X3 homomultimer and P2X2/3 heteromultimer receptors on sensory nerves in a wide range of organs, including skin, tongue, tooth pulp, intestine, bladder, and ureter that mediate the initiation of pain. Purinergic mechanosensory transduction has been proposed for visceral pain, where ATP released from epithelial cells lining the bladder, ureter, and intestine during distension acts on P2X3 and P2X2/3, and possibly P2Y, receptors on subepithelial sensory nerve fibers to send messages to the pain centers in the brain as well as initiating local reflexes. P1, P2X, and P2Y receptors also appear to be involved in nociceptive neural pathways in the spinal cord. P2X4 receptors on spinal microglia have been implicated in allodynia. The involvement of purinergic signaling in long-term neuropathic pain and inflammation as well as acute pain is discussed as well as the development of P2 receptor antagonists as novel analgesics.
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PMID:Purinergic P2 receptors as targets for novel analgesics. 1622 12

We have recently demonstrated that the P2X4 receptor, an ATP-gated cation channel, in spinal microglia is a key molecule that mediates the mechanical allodynia induced by peripheral nerve injury. Although microglial P2X4 receptor expression is increased after peripheral nerve injury, the molecular mechanism(s) underlying its upregulation remains largely unknown. Fibronectin is a member of the extracellular matrix molecules and is actively produced in response to injury and diseases in the CNS. Here, we describe the influence of fibronectin on P2X4 receptor expression in microglia and the upregulation of fibronectin after peripheral nerve injury. Microglia that were cultured on fibronectin-coated dishes showed a marked increase in P2X4 receptor expression, both at the mRNA and protein levels, as compared to those cultured on control dishes. Fibronectin also enhanced the microglial Ca2+ responses mediated by P2X4 receptors. Moreover, Western blot examination of the spinal cord from a rat with spinal nerve injury indicated that fibronectin was upregulated on the ipsilateral side. Interestingly, intrathecal injection of ATP-stimulated microglia to the rat lumber spinal cord revealed that microglia cultured on fibronectin-coated dishes was more effective in the induction of allodynia than microglia cultured on control dishes. Taken together, our results suggest that spinal fibronectin is elevated after the peripheral nerve injury and it may be involved in the upregulation of the P2X4 receptor in microglia, which leads to the induction of neuropathic pain.
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PMID:Possible involvement of increase in spinal fibronectin following peripheral nerve injury in upregulation of microglial P2X4, a key molecule for mechanical allodynia. 1653 77


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