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)

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.
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PMID:Co-activation of P2Y2 receptor and TRPV channel by ATP: implications for ATP induced pain. 1613 36

The distribution and modulation of the P2X(3) receptor was studied in trigeminal ganglion neurons to provide insight into the role of ATP in craniofacial sensory mechanisms. Binding to the d-galactose specific lectin IB4 was found in 73% of P2X(3)-positive neurons while only 16% of IB4 neurons expressed P2X(3). Neurons expressing P2X(3) alone were significantly larger than IB4-or IB4/P2X(3)-positive neurons. Investigation of target-specificity revealed that 22% of trigeminal ganglion muscle afferent neurons were positive for P2X(3) versus 16% of cutaneous afferent neurons. Muscle P2X(3) afferents were significantly smaller than the overall muscle afferent population while P2X(3) cutaneous afferent neurons were not. Presumptive heteromeric (P2X(2/3)) muscle afferent neurons were also identified and comprised 77% of the P2X(3) muscle afferent population. Muscle afferent neurons co-expressed P2X(3) with either calcitonin gene-related peptide (15%) or substance P (4%). The number of P2X(3)-positive muscle afferent neurons significantly increased one and four days following complete Freund's adjuvant-induced masseter muscle inflammation, but significantly decreased after 12 days. These results indicate that within trigeminal ganglia: (1) the P2X(3) receptor is expressed in both small and medium-sized neurons; (2) the P2X(3) receptor is not exclusively expressed in IB4 neurons; (3) P2X(3) is co-expressed with neuropeptides; (4) differences in the proportion of cutaneous versus muscle P2X(3) afferents are not apparent. Trigeminal P2X(3) neurons therefore differ markedly from dorsal root ganglion P2X(3) afferents. This study also shows that deep tissue inflammation modulates expression of the P2X(3) receptor and thus may warrant exploration as a target for therapeutic intervention.
Pain 2005 Oct
PMID:Trigeminal P2X3 receptor expression differs from dorsal root ganglion and is modulated by deep tissue inflammation. 1615 75

It has been well known that pain is caused by nociceptive stimulation such as protons (i.e. acidic solutions), heat and capsaicin, a pungent ingredient of chilli peppers. For a long period, the signal transduction mechanism of pain activated by these nociceptive stimuli has not been clarified. Recent advance, especially the identification of TRPV1 receptor (for which capsaicin, protons and heat are ligands), P2X and P2Y receptor (for which ATP is a ligand) and acid sensing ion channel made a remarkable progress in understanding the mechanism of nociceptive neurons. This article reviews the structures and functions of nociceptive neuronal system particularly in TRPV1 receptor, P2X and P2Y receptors.
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PMID:[Structure and function of nociceptive neuronal receptors]. 1621 80

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

Progressive loss of pain perception and cutaneous nerve fibers are frequently observed in diabetic patients. We evaluated the feasibility of using thy1-YFP mice that express the yellowish-green fluorescent protein (YFP) in all of their sensory/motor neurons for noninvasive monitoring of cutaneous nerve fiber loss during diabetes. Fluorescent fibers in skin sections from the leg of thy1-YFP mice stained positive for the neuron-specific protein gene product 9.5 (PGP9.5), indicating that the cutaneous fluorescent fibers are indeed nerve fibers. In diabetic thy1-YFP mice, significant small cutaneous nerve fiber loss in the leg was observed at 3 months following the onset of diabetes, but loss of heat-induced pain perception occurred as early as 1 month following the onset of diabetes, indicating that functional impairment of sensory nerves precedes cutaneous nerve fiber loss. Immunostaining of skin sections of mice killed at 6 months following the onset of diabetes showed that parallel to the loss of small fluorescent nerve fibers, there was a significant decrease in fibers stained positive for calcitonin gene-related peptide, substance P, and purinoreceptor subtype in diabetic thy1-YFP mice. These mice will be useful for noninvasive monitoring of cutaneous nerve fiber degeneration and loss of heat-induced pain perception during diabetes and for the assessment of efficacy of therapeutic treatment of diabetic neuropathy.
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PMID:Noninvasive monitoring of diabetes-induced cutaneous nerve fiber loss and hypoalgesia in thy1-YFP transgenic mice. 1624 33

P2X3 and P2X2/3 receptors in dorsal root ganglia (DRG) appear to participate in producing nociceptive responses after nerve injury. However, the mechanisms underlying the receptor-mediated nociception in the neuropathic state remain unclear. Using spared nerve injury (SNI) rats, we found that allodynic and nocifensive (flinch) behavioral responses developed after injury can be reversed by P2X receptor antagonists, indicating an involvement of P2X receptors. Immunocytochemical studies revealed that P2X3 receptors are expressed in small and medium but rarely in large DRG neurons of both normal and SNI rats. Thus, contrary to the conventional view that only large A beta cells mediate allodynia, small and medium cells are intimately involved in P2X3 receptor-mediated allodynia. Measuring ATP levels in the subcutaneous space of the rat paw, we showed that ATP release does not change after SNI. On the other hand, the P2X receptor agonist, alpha beta-methylene ATP produces 3.5-fold larger flinch responses at a 8.0-fold lower dose. Thus, sensitization of P2X3 receptors rather than a change in ATP release is responsible for the neuropathic pain behaviors. We further demonstrated that sensitization of P2X3 receptors arises from an increase in receptor function. ATP-induced P2X3 receptor-mediated currents in DRG neurons is 2.5-fold larger after SNI. The expression of P2X3 receptors on the cell membrane is significantly enhanced while the total expression of P2X3 receptors remained unchanged. Thus, the enhancement of trafficking of P2X3 receptors is likely an important mechanism contributing to the increase in receptor function after nerve injury.
Pain 2005 Dec 15
PMID:Mechanisms underlying enhanced P2X receptor-mediated responses in the neuropathic pain state. 1629 67

The present study examined noradrenaline-induced modulation of ATP-evoked currents in dorsal root ganglion (DRG) neurons after sciatic nerve injury (transection). ATP (10 microM) generated fast/mixed type of whole-cell membrane currents, possibly as mediated via P2X(3)/P2X(3)-like receptors, and slow type of the currents, possibly as mediated via P2X(2/3) receptors, in acutely dissociated L4/5 DRG neurons, without significant difference between sham and injury group. For sham group, noradrenaline (10 microM) enhanced fast/mixed type of ATP-evoked currents in ipsilateral DRG neurons, that is not inhibited by H-7, a broad inhibitor of protein kinases, but otherwise it had no effect on slow type of the currents. For injury group, noradrenaline (10 microM) significantly potentiated slow type of ATP-evoked currents in ipsilateral DRG neurons, that is abolished by H-7 or GF109203X, a selective inhibitor of protein kinase C (PKC), while it depressed fast/mixed type of the currents. In the analysis of real-time reverse transcription-polymerase chain reaction, an increase in the mRNAs for alpha(1b), alpha(2a), alpha(2d), and beta(2) adrenergic receptors was found with the ipsilateral DRGs after sciatic nerve injury. Collectively, the results of the present study suggest that noradrenaline potentiates P2X(2/3) receptor currents by activating PKC via alpha(1) adrenergic receptors linked to G(q) protein, perhaps dominantly alpha(1b) adrenergic receptors, in DRG neurons after sciatic nerve injury. This may account for a nociceptive pathway in response to noradrenergic sprouting after peripheral nerve injury.
Pain 2006 Jan
PMID:Modulation of P2X receptors via adrenergic pathways in rat dorsal root ganglion neurons after sciatic nerve injury. 1636 Feb 72

Presynaptic ionotropic glutamate receptors are increasingly attributed a role in the modulation of sensory input at the first synapse of dorsal root ganglion (DRG) neurons in the spinal dorsal horn. Central terminals of DRG neurons express AMPA and NMDA receptors whose activation modulates the release of glutamate, the main transmitter at these synapses. Previous work, with an antibody that recognizes all low-affinity kainate receptor subunits (GluR5, 6, 7), provided microscopic evidence of presynaptic kainate receptors in unidentified primary afferent terminals in superficial laminae of the spinal dorsal horn (Hwang SJ, Pagliardini S, Rustioni A, Valtschanoff JG. Presynaptic kainate receptors in primary afferents to the superficial laminae of the rat spinal cord. J Comp Neurol 2001; 436: pp. 275-289). We show here that, although all such subunits may be expressed in these terminals, GluR5 is the subunit most readily detectable at presynaptic sites in sections processed for immunocytochemistry. We also show that the high-affinity kainate receptor subunits KA1 and KA2 are expressed in central terminals of DRG neurons and are co-expressed with low-affinity receptor subunits in the same terminals. Quantitative data show that kainate-expressing DRG neurons are about six times more likely to express the P2X(3) subunit of the purinergic receptor than to express substance P. Thus, nociceptive afferents that express presynaptic kainate receptors are predominantly non-peptidergic, suggesting a role for these receptors in the modulation of neuropathic rather than inflammatory pain.
Pain 2006 Jan
PMID:Presynaptic low- and high-affinity kainate receptors in nociceptive spinal afferents. 1636 Feb 75

Butyl benzyl phthalate (BBP) is a plasticizer and causes public concern because of its genomic estrogenic effects via estrogen receptors. We previously found that BBP has non-genomic effects, exerting inhibitory effects on the functional activities of nicotinic acetylcholine receptors (nAChR) in bovine adrenal chromaffin cells. nAChR belongs to the superfamily of neurotransmitter-gated channels, so does P2X purinoceptor that is widely distributed in the nervous system and play a role in pain reactions. In this study, we investigated the effects of BBP on the change of [Ca2+]c (cytosolic calcium ion concentration) under the stimulation of purinoceptors in PC12 cells and found that BBP inhibited ATP-induced [Ca2+]c rise (IC50=8.3 microM). The inhibitory rate of BBP remained under the increase of ATP concentration; therefore, the possibility of competitive inhibition was excluded. The inhibition of BBP on P2Y was excluded because its inhibition on ATP-induced [Ca2+]c rise was not found in the absence of extracellular Ca2+. BBP might have some actions on voltage-operated Ca2+ channels (VOCCs) since BBP inhibited the Ca2+ signaling responding to high K+ stimulation (IC50=1.2 microM). We suggest that BBP inhibits the ATP-induced [Ca2+]c rise via its non-competitive inhibition on P2X purinoceptors and VOCCs in the plasma membrane.
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PMID:Butyl benzyl phthalate blocks Ca2+ signaling coupled with purinoceptor in rat PC12 cells. 1636 Jul 12

Acute systemic administration of a novel and highly selective non-nucleotide P2X(3)/P2X(2/3) receptor antagonist, A-317491, has been shown to reduce chronic hyperalgesia and allodynia in several animal models of pathological pain in the absence of cardiovascular and CNS side effects. Furthermore, these studies have also outlined the antinociceptive profile for a P2X(3)/P2X(2/3) receptor antagonist, as A-317491 was effective in models of chronic inflammatory and neuropathic pain, but not in models of acute, acute inflammatory or visceral pain. The development of A-317491 has also added to the current understanding of P2X(3)/P2X(2/3) receptor pharmacology and its contributions to nociceptive transmission and modulation. To this end, recent studies have demonstrated that both spinal and peripheral P2X(3)/P2X(2/3) receptors have significant but differential contributions to nociception in animal models of nerve or tissue injury, and that antagonism of spinal P2X(3)/P2X(2/3) receptors results in an indirect activation of the opioid system to alleviate inflammatory thermal hyperalgesia and chemogenic nociception. Thus, preclinical data have shown considerable promise for the utility of a P2X(3)/P2X(2/3) receptor antagonist to alleviate various forms of chronic pain. Furthermore, the discovery of this selective and metabolic stable antagonist for P2X(3)/P2X(2/3) receptors has also been useful in defining the contributions of these receptors to states of pathological pain.
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PMID:Antinociceptive properties of a non-nucleotide P2X3/P2X2/3 receptor antagonist. 1639 20


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