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

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

Extracellular ATP has been known to activate sensory neurons via the ATP-gated ion channels P2X receptors, indicating that the P2X receptors may play a role in signal transduction of pain from the periphery to the spinal cord in vivo. Here, we found a novel nociceptive response induced by ATP, mechanical allodynia (hypersensitivity to innocuous mechanical stimulus). Injection of alpha,beta-methylene ATP (alpha(beta)meATP), an agonist to P2X receptor, into plantar surface in rats produced the mechanical allodynia along with previously described nocifensive behavior and thermal hyperalgesia. This allodynic response was blocked by pretreatment with the P2 receptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate. Interestingly, only the mechanical allodynia evoked by alpha(beta)meATP selectively remained in neonatal capsaicin-treated adult rats that had selectively lost the capsaicin-sensitive neurons. ATP has been shown to produce two distinguishable electrophysiological responses (inward currents with rapid and slow desensitization) in dorsal root ganglion (DRG) neurons. In the present electrophysiological experiment, the percentage of DRG neurons that responded to alpha(beta)meATP with slow desensitizing inward current remained constant in capsaicin-treated rats, whereas the percentage that responded with rapid desensitizing current dramatically decreased. Taken together with our previous finding that the alpha(beta)meATP-activated slow desensitizing current in DRG neurons is mediated by heteromeric P2X2/3 (P2X2 and P2X3) receptors, it is hypothesized that activation of heteromeric P2X2/3 receptors in peripheral terminals of capsaicin-insensitive primary afferent fibers leads to the induction of mechanical allodynia.
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PMID:Mechanical allodynia caused by intraplantar injection of P2X receptor agonist in rats: involvement of heteromeric P2X2/3 receptor signaling in capsaicin-insensitive primary afferent neurons. 1089 77

Extracellular ATP is implicated in numerous sensory processes ranging from the response to pain to the regulation of motility in visceral organs. The ATP receptor P2X3 is selectively expressed on small diameter sensory neurons, supporting this hypothesis. Here we show that mice deficient in P2X3 lose the rapidly desensitizing ATP-induced currents in dorsal root ganglion neurons. P2X3 deficiency also causes a reduction in the sustained ATP-induced currents in nodose ganglion neurons. P2X3-null mice have reduced pain-related behaviour in response to injection of ATP and formalin. Significantly, P2X3-null mice exhibit a marked urinary bladder hyporeflexia, characterized by decreased voiding frequency and increased bladder capacity, but normal bladder pressures. Immunohistochemical studies localize P2X3 to nerve fibres innervating the urinary bladder of wild-type mice, and show that loss of P2X3 does not alter sensory neuron innervation density. Thus, P2X3 is critical for peripheral pain responses and afferent pathways controlling urinary bladder volume reflexes. Antagonists to P2X3 may therefore have therapeutic potential in the treatment of disorders of urine storage and voiding such as overactive bladder.
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PMID:Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. 1106 62

ATP activates damage-sensing neurons (nociceptors) and can evoke a sensation of pain. The ATP receptor P2X3 is selectively expressed by nociceptors and is one of seven ATP-gated, cation-selective ion channels. Here we demonstrate that ablation of the P2X3 gene results in the loss of rapidly desensitizing ATP-gated cation currents in dorsal root ganglion neurons, and that the responses of nodose ganglion neurons to ATP show altered kinetics and pharmacology resulting from the loss of expression of P2X(2/3) heteromultimers. Null mutants have normal sensorimotor function. Behavioural responses to noxious mechanical and thermal stimuli are also normal, although formalin-induced pain behaviour is reduced. In contrast, deletion of the P2X3 receptor causes enhanced thermal hyperalgesia in chronic inflammation. Notably, although dorsal-horn neuronal responses to mechanical and noxious heat application are normal, P2X3-null mice are unable to code the intensity of non-noxious 'warming' stimuli.
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PMID:Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors. 1106 62

Membrane currents in response to the application of alpha, beta-methylene ATP (alpha,beta-meATP) were recorded by the whole-cell patch-clamp technique in human embryonic kidney 293 cells transfected with the human P2X3 receptor (HEK 293-hP2X3 cells). Trichloroethanol, the biologically active metabolite of chloral hydrate, but not ethanol itself concentration-dependently and reversibly inhibited the current responses. It was concluded that the reported analgesic effect of chloral hydrate may be due to the interruption of pain transmission in dorsal root ganglia expressing P2X3 receptors.
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PMID:Trichloroethanol inhibits ATP-induced membrane currents in cultured HEK 293-hP2X3 cells. 1110 30

Extracellular ATP has been known to activate sensory neurons via the ATP-gated ion channels P2X receptors, leading to the proposal that the P2X receptors may play a role in signal transduction of pain from the peripheral site to the spinal cord in vivo. P2X3 receptors are expressed in capsaicin-sensitive small-sized dorsal root ganglion (DRG) neurons, and they are involved in the generation of rapidly desensitizing inward current and evoking nocifensive behavior and thermal hyperalgesia. Heteromeric P2X2/3 (P2X2 and P2X3) receptor is expressed in capsaicin-insensitive primary afferent fibers, and its activation leads to the generation of slow desensitizing currents and induction of mechanical allodynia. In addition, accumulating information suggests the involvement of G protein-coupled ATP receptors in the modulation of the generation and transmission of pain.
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PMID:[ATP receptors in pain]. 1118 2

Receptor subtypes for purines have been identified in a variety of tissues, increasing interest in the roles of purine-mediated signalling in pathophysiological processes. Growing evidence supports the involvement of one of the purinoceptor subtypes, P2X3, in nociception. In this article, recent studies of purine-mediated nociception and visceral pain will be discussed. Furthermore, a novel hypothesis is proposed for purine-mediated mechanosensory transduction where ATP released during distension from epithelial cells lining tubes (such as ureter and gut) and sacs (such as the bladder) acts on P2X3 receptors on a subepithelial nerve plexus to initiate impulses that are relayed via the spinal cord to pain centres in the brain.
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PMID:Purine-mediated signalling in pain and visceral perception. 1128 18

Evidence is accumulating which supports a role for ATP in the initiation of pain by acting on P2X receptors, in particular P2X3, expressed on nociceptive afferent nerve terminals. To investigate whether this receptor plays a role in dental pain, we studied the presence and distribution of P2X3 receptors in human dental pulp, and their co-localization with other neural markers. Pulps were removed from extracted third molars and immunohistochemically stained with an antibody against P2X3 receptors. P2X3 immunoreactive (-ir) nerve fibers were detected in the main body of the pulp, in the sub-odontoblastic plexus of Raschkow, and within the odontoblastic area. Co-localization of the P2X3-ir neurons with neurofilament protein (NF) showed that the majority of the fibers were positive for both NF and P2X3. Double labeling with isolectin B4 (IB4) showed that all P2X3-ir neurons also bind IB4. We conclude that P2X3 receptors are present on both myelinated and unmyelinated nerve fibers in human dental pulp and may play a role in dental pain mechanisms.
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PMID:Immunohistochemical evidence for ATP receptors in human dental pulp. 1133 36

P2X3 is one receptor of a family of seven ligand-gated ion channels responding to purines. Increasing evidence indicates its involvement in neuronal signaling and in pain. However, there is currently no selective inhibitor known for this subtype. In order to obtain such a specific inhibitor, a variety of antisense oligonucleotides (ASO) against rat P2X3 was tested, and dose-dependent, sequence-specific downregulation of the rat P2X3 receptor (expressed in a Chinese hamster ovary cell line [CHO-K1]) on the mRNA, protein, and functional levels was observed. Using real-time quantitative PCR, a dose-dependent downregulation of P2X3 mRNA by ASO, as compared with untreated and mismatch controls, was demonstrated. Subsequently, downregulation by the two most potent ASO was confirmed at the protein level by Western blot. Sequence specificity was shown by titration of mismatches to the original selected oligonucleotide, and this correlated with progressive loss of P2X3 inhibition. The functional response of the P2X3 receptor was examined using whole-cell voltage clamping. Upon application of 10 microM of a nonspecific agonist, alpha,beta-methylene-ATP (alphabeta meATP), pretreatment with increasing amounts of the most active ASO 5037 correlated with a decrease in depolarization. The ability to specifically downregulate the P2X3 receptor by ASO treatment will allow investigation of the biologic role of this receptor in neuronal tissues and eventually in in vivo models of chronic pain.
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PMID:Specific inhibition of the rat ligand-gated ion channel P2X3 function via methoxyethoxy-modified phosphorothioated antisense oligonucleotides. 1144 92

ATP-gated P2X receptors in nociceptive sensory neurons participate in transmission of pain signals from the periphery to the spinal cord. To determine the role of P2X receptors under injurious conditions, we examined ATP-evoked responses in dorsal root ganglion (DRG) neurons isolated from rats with peripheral inflammation, induced by injections of complete Freund's adjuvant (CFA) into the hindpaw. Application of ATP induced both fast- and slow-inactivating currents in control and inflamed neurons. CFA treatment had no effect on the affinity of ATP for its receptors or receptor phenotypes. On the other hand, inflammation caused a twofold to threefold increase in both ATP-activated currents, altered the voltage dependence of P2X receptors, and enhanced the expression of P2X2 and P2X3 receptors. The increase in ATP responses gave rise to large depolarizations that exceeded the threshold of action potentials in inflamed DRG neurons. Thus, P2X receptor upregulation could account for neuronal hypersensitivity and contribute to abnormal pain responses associated with inflammatory injuries. These results suggest that P2X receptors are useful targets for inflammatory pain therapy.
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PMID:Peripheral inflammation sensitizes P2X receptor-mediated responses in rat dorsal root ganglion neurons. 1175 92


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