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

Classical migraine is associated with two distinct phases; an initial vasoconstriction followed by vasodilatation. The "purinergic" hypothesis for migraine was originally put forward in 1981 as a basis for the reactive hyperaemia and pain during the headache phase. It was suggested that adenosine 5'-triphosphate (ATP) and its breakdown products adenosine 5'-monophosphate and adenosine were strong contenders for mediating the vasodilatation following the initial vasospasm and subsequent hypoxia. ATP was also implicated in the pathogenesis of pain during migraine via stimulation of primary afferent nerve terminals located in the cerebral vasculature. Recent studies have shown that the ATP-induced cerebral vasodilation is endothelium-dependent via activation of P2Y-purinoceptors on the endothelial cell surface and subsequent release of endothelium-derived relaxing factor (EDRF); and that the endothelial cells are the main local source of the ATP involved, although adenosine 5'-diphosphate and ATP released from aggregating platelets may also contribute to this vasodilatation. These findings have extended the "purinergic" hypothesis for migraine in two ways. Firstly, they have clarified the mechanism of purinergic vasodilatation during the headache phase of migraine. Secondly, they suggest that a purinergic mechanism may also be involved in the initial local vasospasm, via P2X-purinoceptors on smooth muscle cells occupied by ATP released either as a cotransmitter with noradrenaline from perivascular sympathetic nerves or from damaged endothelial cells.
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PMID:The role of adenosine triphosphate in migraine. 270 Dec 87

There have been hints over the years about the involvement of purines in pain, and we now have direct evidence with the cloning and characterisation of extracellular receptors for ATP (P2X-purinoceptors) on nociceptive sensory neurons. In this article, a hypothesis is put forward about the sources of ATP released to activate these receptors in three different pain conditions--as a cotransmitter from sympathetic nerves in causalgia and reflex sympathetic dystrophy; from endothelial cells in vascular pain, including migraine and angina; and from tumour cells in cancer. These findings are leading to an active search for selective P2-purinoceptor antagonists to alleviate pain.
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PMID:A unifying purinergic hypothesis for the initiation of pain. 866 73

The recent discovery of a P2X purinoceptor (a ligand-gated ion channel triggered by ATP) that is selectively expressed by small-diameter sensory neurons has led to the exploration of the sources of ATP involved in the initiation of different types of nociception and pain, including sympathetic nerves, endothelial cells and tumour cells. In addition, the anti-nociceptive actions of adenosine via prejunctional P1(A1) purinoceptors in the spinal cord and the pain-enhancing actions of adenosine via P1(A2) purinoceptors in the periphery have generated great interest in the development of P1 agonists and antagonists, as well as P2X antagonists as potential analgesic drugs.
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PMID:Purinergic receptors: their role in nociception and primary afferent neurotransmission. 879 2

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

The pronociceptive effects of adenosine 5'-triphosphate (ATP) were examined in the low concentration formalin model (0.5%) by coadministration of ATP, ATP analogs (alpha,beta-methylene-ATP and 2-methylthio-ATP) and antagonists (suramin, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid) with formalin and determining effects on the expression of flinching behaviours. Coadministration of ATP (5-500 nmol) with formalin enhanced phase 2 (12-60 min after injection) but not phase 1 (0-10 min after injection) responses. alpha,beta-methylene-ATP (0.5-50 nmol) but not 2-methylthio-ATP (50-500 nmol) produced a similar enhancement of activity, generating an order of potency of alpha,beta-methylene-ATP, ATP >> 2-methylthio-ATP. This enhancement was primarily expressed in the latter part of phase 2, 30-60 min after injection. Coadministration of suramin 50-500 nmol, a non-selective P2X and P2Y purinoceptor antagonist and pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid 5-500 nmol, a selective P2X purinoceptor antagonist, dose-dependently inhibited the augmentation of the formalin response by ATP 50 nmol, but did not reduce the response to formalin itself. Pretreatment for 30 min with higher doses of suramin inhibited the response to formalin (0.5%, 1.5%) and this appeared to be by a systemically mediated action as it was seen following administration into the contralateral paw. The results of this study provide evidence in support of a P2X purinoceptor mediated augmentation of the pain signal by ATP. The delayed time-course of the effect suggests that it may occur in concert with other mediators that are recruited by the inflammatory process, rather than reflecting a direct depolarization of sensory nerves. Other behavioural paradigms may be required to examine the fast onset, direct effect. Suramin appears to exert both local and systemic effects on the expression of pain behaviours in response to formalin.
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PMID:Peripheral adenosine 5'-triphosphate enhances nociception in the formalin test via activation of a purinergic p2X receptor. 925 43

Painful stimuli to the skin initiate action potentials in the peripheral terminals of dorsal root ganglion (DRG) neurons. These action potentials propagate to DRG central terminals in the dorsal horn of the spinal cord, evoking release of excitatory transmitters such as glutamate onto postsynaptic dorsal horn neurons. P2X receptors, a family of ligand-gated ion channels activated by the endogenous ligand ATP, are highly expressed by DRG neurons. Immunoreactivity to P2X receptors has been identified in the dorsal horn superficial laminae associated with nociceptive DRG central terminals, suggesting the presence of presynaptic P2X receptors. Here we have used a DRG-dorsal horn co-culture system to show that P2X receptors are localized at presynaptic sites on DRG neurons; that activation of these receptors results in increased frequency of spontaneous glutamate release; and that activation of P2X receptors at or near presynaptic DRG nerve terminals elicits action potentials that cause evoked glutamate release. Thus activation of P2X receptors at DRG central terminals can modify sensory signal throughput, and might even initiate sensory signals at central synapses without direct peripheral input. This putative central modulation and generation of sensory signals may be associated with physiological and pathological pain sensation, making presynaptic P2X receptors a possible target for pain therapy.
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PMID:Activation of ATP P2X receptors elicits glutamate release from sensory neuron synapses. 933 89

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

1. We tested the hypothesis that functional P2X receptors are present on peripheral terminals of primary afferent articular nociceptors in the rat knee joint. Neural activity was recorded extracellularly from the medial articular nerve innervating the knee joint in rats anaesthetized with pentobarbitone. 2. The selective P2X receptor agonist, alphabeta methylene ATP (alphabetameATP), and the endogenous ligand, ATP, caused a rapid short-lasting excitation of a sub-population of C and Adelta nociceptive afferent nerves innervating normal knee joints when injected intra-arterially or intra-articularly, and this effect was antagonized by the non-selective P2 receptor antagonist PPADS. 3. Induction of a chronic (14-21 days) unilateral inflammatory arthritis of the knee joint using locally injected Freund's adjuvant neither increased or decreased responsiveness of joint nociceptors to alphabetameATP or ATP. 4. Our results support the hypothesis that alphabetameATP-sensitive P2X receptors are expressed on peripheral nociceptive afferents in the rat knee joint suggesting that they may be involved in the initiation of nociception and pain.
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PMID:P2X receptor-mediated excitation of nociceptive afferents in the normal and arthritic rat knee joint. 978 7

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

In the spinal dorsal horn (DH), transmission and modulation of peripheral nociceptive (pain-inducing) messages involve classical neurotransmitters and neuropeptides. We show that approximately half of DH neurons use ATP as a fast excitatory neurotransmitter acting at ionotropic P2X postsynaptic receptors. ATP was not codetected with glutamate but was coreleased with the inhibitory neurotransmitter GABA. Moreover, adenosine, probably generated by extracellular metabolism of ATP, finely tuned GABAergic inhibitory postsynaptic currents. Differential modulation of excitatory versus inhibitory components of this mixed cotransmission may help to explain changes in sensory message processing in the DH during mechanical hyperalgesia and neuropathic pain.
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PMID:Synaptic corelease of ATP and GABA in cultured spinal neurons. 1019 7


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