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

The initial pain from tissue damage may result from the release of cytoplasmic components that act upon nociceptors, the sensors for pain. ATP was proposed to fill this role because it elicits pain when applied intradermally and may be the active compound in cytoplasmic fractions that cause pain. Moreover, ATP opens ligand-gated ion channels (P2X receptors) in sensory neurons and only sensory neurons express messenger RNA for the P2X3 receptor. To test whether ATP contributes to nociception, we developed a tissue culture system that allows comparison of nociceptive (tooth-pulp afferent) and non-nociceptive (muscle-stretch receptor) rat sensory neurons. Low concentrations of ATP evoked action potentials and large inward currents in both types of neuron. Nociceptors had currents that were similar to those of heterologously expressed channels containing P2X3 subunits, and had P2X3 immunoreactivity in their sensory endings and cell bodies. Stretch receptors had currents that differed from those of P2X3 channels, and had no P2X3 immunoreactivity. These results support the theory that P2X3 receptors mediate a form of nociception, but also suggest non-nociceptive roles for ATP in sensory neurons.
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PMID:Distinct ATP receptors on pain-sensing and stretch-sensing neurons. 916 13

We have shown the presence and activity of ATP-gated ion channels (P2X receptors) in nociceptive nerve endings, supporting the theory that these channels mediate some forms of nociception [Cook S.P., Vulchanova L., Hargreaves K. M., Elde R. and McCleskey E. W. (1997) Distinct ATP receptors on pain-sensing and stretch-sensing neurons. Nature 387, 505-508]. The kinetics and pharmacology of ATP-gated currents in nociceptors suggest that the channels are comprised of either homomeric or heteromeric combinations of P2X3 receptors. Consistent with the diverse nature of P2X structure, electrophysiological responses of rat tooth-pulp nociceptors fall into two distinct classes based on desensitization and recovery kinetics. Here, we quantified the dramatic differences in desensitization kinetics of transient and persistent currents. The major component of transient P2X current desensitized with a tau decay = 32 +/- 2 msec, while persistent current desensitized > 100-fold more slowly, tau decay = 4000 +/- 320 msec. Both currents recovered from desensitization in minutes: tau recovery = 4 min for transient current, and tau recovery = 0.7 +/- 0.2 min for persistent current. Persistent current recovery was often accompanied by a current "overrecovery" that averaged ca threefold magnitude prior to desensitization. Comparison of ATP current in elevated Ca2+ext also revealed differences in transient and presistent currents. In 2 mM Ca2+ext medium, decrease of Na+ext resulted in an almost complete reduction of persistent, but not transient, current. Subsequent elevation of Ca2+ext greatly increased the transient, but not persistent, current. Mechanistic explanations for either the increase in transient current magnitude by elevated Ca2+ext, or persistent current overrecovery may reflect endogenous pathways for P2X receptor modulation.
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PMID:Desensitization, recovery and Ca(2+)-dependent modulation of ATP-gated P2X receptors in nociceptors. 936 85

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

Nerve endings of nociceptors (pain-sensing neurons) express an unusual subtype of ATP-gated ion channel, the P2X3 receptor, that rapidly desensitizes (<100 msec) and slowly recovers (>20 min). Here we show that Ca2+, or certain other polyvalent cations, binds to an extracellular site on rat sensory neurons and can increase current through P2X3 channels more than 10-fold. Importantly, Ca2+ facilitates P2X3 current to precisely the same level whether a transient Ca2+ change occurred just before or several minutes before activating the channels with ATP. This memory for past changes in Ca2+ is integrative in that a 90 sec Ca2+ stimulus delivered just before an ATP application has the same effect as an earlier series of three, separated 30 sec Ca2+ stimuli. These diverse phenomena are explained by a single mechanism: Ca2+ speeds recovery of P2X channels from desensitization. Recovery follows an exponential growth curve that depends on the duration, but not the timing, of changes in recovery rate. Modulation of desensitization underlies a well described short-term memory in bacteria, and it might be similarly used in the nervous system.
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PMID:A memory for extracellular Ca2+ by speeding recovery of P2X receptors from desensitization. 980 63

P2X3 purinoceptor cellular distribution was studied in rat sensory neurons in naive animals and following peripheral nerve injury using immunohistochemical methods. Specific antiserum was raised in rabbits and characterized by Western blot, absorption assays and labeling of recombinant receptors. In naive animals, P2X3 immunoreactivity was present predominantly in a subpopulation of small-diameter sensory neurons in dorsal root ganglia. In the spinal cord, immunoreactivity was observed in the superficial laminae of the dorsal horn. Following a chronic constriction injury to the sciatic nerve, the number of P2X3 positive small and medium diameter neurons increased in dorsal root ganglia when compared with sham-operated animals. In addition, the spinal cord immunoreactivity increased in magnitude on the side ipsilateral to the ligated nerve, consistent with up-regulation of receptors in presynaptic terminals of the primary sensory neurons.
Pain 1999 Mar
PMID:Immunocytochemical localization of P2X3 purinoceptors in sensory neurons in naive rats and following neuropathic injury. 1020 40

P2X receptors have been suggested to play a role in the transduction of sensory signals such as pain and sound. In the present study, polyclonal antibodies against P2X1 to P2X6 receptors were used to localize P2X receptors in circumvallate and fungiform papillae of rats. Nerve fibres innervating the taste buds stained intensely with P2X3 receptor antibodies. P2X3 receptor-positive nerves were observed in the intra- and subgemmal regions. The nerve fibres were also stained with P2X2 receptor antibodies, but the intensity was much lower. The distribution of P2X2 receptor immunoreactivity overlaps with that of P2X3. These results suggest that ATP might be a neurotransmitter in taste reception cells in the taste buds, where it transducts the taste signals to the afferent taste nerves by activating P2X receptors at the synapses. This is the first experiment indicating such a role for ATP, although supplementary functional studies are required.
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PMID:Localization of ATP-gated P2X2 and P2X3 receptor immunoreactive nerves in rat taste buds. 1032 92

1. The aim of the present study is to characterize the role of spinal endogenous ATP and P2X receptors in the generation of neurogenic and inflammatory pain. We examined the effects of intrathecal treatment with P2X receptor antagonists on the formalin- and capsaicin-induced nociceptive behaviours in mice. 2. Intrathecal pretreatment with the general P2 receptor antagonist, pyridoxal-phosphate-6-azophenyl-2', 4'-disulphonic acid (PPADS), significantly suppressed both the first and second phases of the formalin-induced nociceptive behaviour. The second phase of the nociceptive response was also suppressed by intrathecal treatment with PPADS after the first phase. Furthermore, pretreatment with the selective antagonist for the P2X1, P2X3 and P2X2+3 receptors, 2',3'-O-(2,4,6-trinitrophenyl)adenosine 5'-triphosphate (TNP-ATP), significantly reduced the first phase, but not the second phase. The second phase was also not suppressed by intrathecal TNP-ATP after the first phase. 3. Capsaicin-induced nociceptive behaviour that has been shown to be a model for neurogenic pain, was also significantly suppressed by intrathecal pretreatment with PPADS or TNP-ATP. 4. Nociceptive behaviour in the first phase of the formalin test and in the capsaicin test were significantly inhibited by intrathecal pretreatment with alpha, beta-methylene ATP (alpha,betameATP: 5 microg mouse-1) 15 min prior to injection of formalin or capsaicin. This treatment has been previously shown to desensitize spinal P2X3 receptor subtypes in vivo. 5. These findings suggest that spinal endogenous ATP may play a role in (1) the formalin- and capsaicin-induced neurogenic pain via the PPADS- and TNP-ATP-sensitive P2X receptors which are also desensitized by alpha,betameATP (perhaps the P2X3 receptor subtype) and (2) formalin-induced inflammatory pain via PPADS-sensitive, TNP-ATP- and alpha,betameATP-insensitive P2X (and/or P2Y) receptors.
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PMID:Evidence for the involvement of spinal endogenous ATP and P2X receptors in nociceptive responses caused by formalin and capsaicin in mice. 1060 29

New analgesic drugs are necessary because a number of pain states are untreatable. Genetic approaches to the identification of analgesic drug targets include mapping genes involved in human pain perception (e.g., trkA involved in hereditary neuropathies), identifying regulators of sensory neuron function in simple multicellular organisms and then investigating the activity of their mammalian homologs (e.g., POU domain transcription factors that specify sensory cell fate), as well as difference, expression, and homology cloning of receptors, ion channels, and transcription factors present in sensory neurons. After target validation through the construction of null mutant mice, high-throughput cell-based screens can be used to identify potential drug candidates. As a result of these approaches, a number of receptors and ion channels present in sensory neurons such as voltage-gated sodium channels [sensory neuron specific (SNS) and Na channel novel] and ATP-gated (P2X3), capsaicin-gated [vanilloid receptor 1(VR1)], and proton-gated [acid-sensing ion channel (ASIC)] channels are now under investigation as potential new analgesic drug targets.
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PMID:Pathobiology of visceral pain: molecular mechanisms and therapeutic implications. II. Genetic approaches to pain therapy. 1076 3

A novel in vitro intra-arterially perfused adult rat tongue-nerve preparation was used to explore the possible actions of P2X purinoceptor agonists (ATP and alpha,beta-methylene ATP (alpha, beta-meATP)) on sensory nerve terminals innervating the rat tongue. We made whole-nerve recordings of the trigeminal branch of the lingual nerve (LN), which conducts general sensory information (pain, temperature, touch, etc.), and the chorda tympani (CT), which conducts taste information. Changes in LN and CT activity following intra-arterial application of P2X agonists were compared. In seven preparations, bolus close-arterial injection of ATP (30-3000 microM, 0.1 ml) or alpha,beta-meATP (10-300 microM, 0.1 ml) induced a rapid (< 1 s after injection), dose-related increase in LN activity that decayed within a few seconds. The minimal concentration of ATP (100 microM) required to elicit a response was about 10-fold higher than that of alpha,beta-meATP (10 microM). Bolus injection of ATP or alpha,beta-meATP induced a moderate decrease in firing frequency in three of seven CT preparations. LN responses to P2X agonists showed signs of rapid desensitisation with the peak frequency of discharge being smaller when the agonists were applied at short intervals. Suramin (200 microM) or PPADS (200 microM) applied by intra-arterial perfusion each antagonised the rapid increase in LN activity following application of alpha,beta-meATP (100 microM). Capsaicin (10 microM, 0.1 ml, n = 5 preparations) was injected intra-arterially to desensitise nociceptive fibres. This was found to block (n = 2) or greatly reduce (n = 3) the excitatory effects of alpha,beta-meATP (100 microM, 0.1 ml) on LN activity, implying that only capsaicin-sensitive nociceptive fibres in LN were responsive to P2X agonists. In contrast to the consistent excitatory responses in LN activity following fast application of P2X agonists as bolus, a variable and moderate change in discharge rate of LN and no change in CT activity (n = 5) was observed after applying ATP (100-300 microM, n = 21) or alpha,beta-meATP (100-300 microM, n = 14) by intra-arterial perfusion. The variable responses in LN activity to slow perfusion in contrast to close-arterial bolus injection are consistent with activation of the rapidly desensitising P2X3 receptors. In summary, ATP and alpha,beta-meATP preferentially activate general sensory afferent fibres (LN) but not taste fibres (CT). We suggest that the increase in whole-nerve activity of LN following application of P2X agonists represents activation of nociceptive fibres which possess P2X3 receptors. Our data indicate that ATP and P2X3 receptors may play a role in nociception, rather than taste sensation in the tongue.
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PMID:P2X purinoceptor-mediated excitation of trigeminal lingual nerve terminals in an in vitro intra-arterially perfused rat tongue preparation. 1079 Jan 66

The ATP-gated cation channel P2X3 is expressed selectively by rat sensory neurones, and may play a role in nociception by binding ATP released from damaged or inflamed tissues. However, the distribution of this channel in human sensory neurons is not known. Using a specific antibody, we have demonstrated intense P2X3 immunoreactivity within a subset (60%) of small/medium diameter sensory neurones and fine nerve fibres in intact post-mortem human dorsal root ganglia (DRG). Co-localization studies showed < 15% overlap with the trkA immunostaining in DRG, indicating that P2X3 was expressed predominantly in sensory neurons that are also isolectin B4 positive. There was a significant decrease in numbers of P2X3-like immunoreactive neurons in human DRG after central axotomy (to 36%), similar to the decrease in rat DRG after peripheral axotomy. However, Western blotting demonstrated a specific 66 kDa band in human DRG and peripheral organs, including intestine, where histochemistry showed P2X3 immunoreactivity in myenteric plexus neurons. Thus P2X3 antagonists may be analgesic, but are unlikely to have a selective effect on pain in humans.
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PMID:P2X3 receptor in injured human sensory neurons. 1079 Aug 70


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