Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0184567 (acute pain)
 3,962 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In 1995 the P2X3 receptor was found to be expressed at high levels in nociceptive sensory neurones, consistent with earlier reports that ATP induced pain in humans and animals. At first it was thought that ATP was most likely to play a role in acute pain, following its release from damaged or stressed cells and since then a wide variety of experimental techniques and approaches have been used to study this possibility. Whilst it is clear that exogenous and endogenous ATP can indeed acutely stimulate sensory neurones, more recent reports using gene knockout and antisense oligonucleotide technologies, and a novel, selective P2X3 antagonist, A-317491, all indicate that ATP and P2X3 receptors are more likely to be involved in chronic pain conditions, particularly chronic inflammatory and neuropathic pain. These reports indicate that P2X3 receptors on sensory nerves may be tonically activated by ATP released from nearby damaged or stressed cells, or perhaps from the sensory nerves themselves. This signal, when transmitted to the CNS, will be perceived consciously as chronic pain. In addition, it is now clear that several subtypes of P2Y receptor are also expressed in sensory neurones. Although their distribution and functions have not been as widely studied as P2X receptors, the effects that they mediate indicate that they might also be considered as therapeutic targets in the treatment of pain. Although our ability to treat persistent painful conditions, such as chronic inflammatory and neuropathic pain, has improved in recent years, these conditions are often resistant to currently available therapies, such as opioids or non-steroidal anti-inflammatory drugs. This reflects a limited understanding of the underlying pathophysiology. It is now clear that the development and maintenance of chronic pain are mediated by multiple factors, but many of these factors, and the receptors and mechanisms through which they act, remain to be identified. Chronic pain is debilitating and can greatly decrease quality of life, not just due to the pain per se, but also because of the depression that can often ensue. Thus a greater understanding of the mechanisms that underlie chronic pain will help identify new targets for novel analgesics, which will be of great therapeutic benefit to many people.
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PMID:Crossing the pain barrier: P2 receptors as targets for novel analgesics. 1451 72

Important breakthroughs in the understanding regeneration failure in an injured CNS have been made by studies of primary afferent neurons. Dorsal rhizotomy has provided an experimental model of brachial plexus (BP) avulsion. This is an injury in which the central branches of primary afferents are disrupted at their point of entry into the spinal cord, bringing motor and sensory dysfunction to the upper limbs. In the present work, the central axonal organization of primary afferents was examined in control (without lesion) adult Wistar rats and in rats subjected to a C3-T3 rhizotomy. Specific sensory axon subtypes were recognized by application of antibodies to the calcitonin gene-related peptide (CGRP), the P2X3 purinoreceptor, the low-affinity p75-neurotrophin receptor and the retrograde tracer cholera toxin subunit beta (TCbeta). Other subtypes weres labeled with the lectin Griffonia simplicifolia 1B4. Using immunohistochemistry and high resolution light microscopy, brachial plexus rhizotomy in adult rats has proven a reliable model for several neural deficits in humans. This lesion produced different degrees of terminal degeneration in the several types of primary afferents which define sub-populations of sensitive neurons. Between the C6 and C8 levels of the spinal cord,, deafferentation was partial for peptidergic GCRP-positive fibers, in contrast with elimination of non peptidergic and myelinated fibers. Dorsal rhizotomy has provided an adequate experimental model to study sensory alterations such as acute pain and allodynia as well as factors that affect regeneration into the CNS., Therefore, the differential deafferentation response must be considered inr the evaluation of therapies for nociception (pain) and regeneration for brachial plexus avulsion. The anatomical diffierences among the primary afferent subtypes also affect their roles in normal and damaged conditions.
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PMID:Degeneration of primary afferent terminals following brachial plexus extensive avulsion injury in rats. 1549 98

The ability of adenosine 5'-triphosphate (ATP) to evoke acute pain has been known for many years, but its role in nociceptive signaling is only now becoming clear. ATP acts via P2X and P2Y receptors, and of particular importance here is the P2X(3) receptor. It is expressed selectively at high levels in nociceptive sensory neurons, where it forms functional receptors on its own and in combination with the P2X(2) receptor. Recent reports using gene knockout methods; antisense oligonucleotide and small, interfering RNA technologies; and a novel, selective P2X(3) antagonist, A-317491, show that P2X(3) receptors are involved in chronic inflammatory and neuropathic pain. The mRNA for other P2X subunits is also found in sensory neurons, and there is evidence for functional P2X(1/5) or P2X(2/6) heteromers in some of these. These data support the possibility that P2X receptors, particularly the P2X(3) subtype, could be targeted in the search for new, effective analgesics.
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PMID:P2X receptors: targets for novel analgesics? 1606 21

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

There is abundant evidence that extracellular ATP and other nucleotides have an important role in pain signaling at both the periphery and in the CNS. At first, it was thought that ATP was simply involved in acute pain, since ATP is released from damaged cells and excites directly primary sensory neurons by activating their receptors. However, neither blocking P2X/Y receptors pharmacologically nor suppressing the expression of P2X/Y receptors molecularly in sensory neurons or in the spinal cord had an effect on acute physiological pain. The focus of attention now is on the possibility that endogenous ATP and its receptor system might be activated in pathological pain states, particularly in 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; unfortunately, this state is generally resistant to currently available treatments. An important advance in our understanding of the mechanisms involved in neuropathic pain has been made by a recent work demonstrating the crucial role of ATP receptors (i.e., P2X(3) and P2X(4) receptors). In this review, we summarize the role of ATP receptors, particularly the P2X(4) receptor, in neuropathic pain. The expression of P2X(4) receptors in the spinal cord is enhanced in spinal microglia after peripheral nerve injury, and blocking pharmacologically and suppressing molecularly P2X(4) receptors produce a reduction of the neuropathic pain behaviour. Understanding the key roles of ATP receptors including P2X(4) receptors may lead to new strategies for the management of neuropathic pain.
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PMID:ATP receptors in pain sensation: Involvement of spinal microglia and P2X(4) receptors. 1840 95

Nociceptive primary afferents have the capacity to induce a state of increased excitability in the dorsal horn neurons of the spinal cord. It is well accepted that capsaicin-sensitive C-fibers transduce noxious stimulation and acute pain and that capsaicin-insensitive A beta-fibers are responsible for touch and innocuous sensation. It has been reported that the intrathecal (i.t.) administration of prostaglandin F(2 alpha) (PGF(2 alpha)) and ATP induces mechanical allodynia via the capsaicin-insensitive primary afferent pathway. In the present study, we investigated the interaction of purinoceptor P2X and the PGF(2 alpha) receptor (FP) in the induction of allodynia by use of mice lacking FP (FP(-/-)). Both PGF(2 alpha) and the P2X receptor agonist alphabeta-methylene ATP administered i.t. strongly induced allodynia for 50 min by tactile stimuli to the flank of mice. The allodynia induced by alphabeta-methylene ATP, but not that by PGF(2 alpha), was suppressed by simultaneous i.t. administration of P2X receptor antagonists pyridoxalphosphate-6-azophenyl-2,4-disulphonic acid and A-317491. In contrast, the allodynia induced by alphabeta-methylene ATP as well as that by PGF(2 alpha) was not observed in FP(-/-) mice. Immunostaining of beta-galactosidase, a reporter knocked into the endogenous FP locus in FP(-/-) mice, showed that the FP receptor was co-localized with P2X(2) and P2X(3) receptors in neurons of the spinal cord. alphabeta-Methylene ATP evoked a transient or sustained [Ca(2+)](i) increase in most of the PGF(2 alpha)-responsive cells in the deeper layer of the spinal cord, and the alphabeta-methylene ATP-evoked increase was blocked by the FP receptor antagonist AL-8810 in two-thirds of the cells. Neither PGF(2 alpha) nor alphabeta-methylene ATP induced the activation of spinal microglia. The present study demonstrates that the alphabeta-methylene ATP-evoked allodynia is mediated by the FP receptor, possibly via the functional coupling between the activation of P2X(2/3) receptors on the central terminal of capsaicin-insensitive fibers and FP receptors on spinal neurons.
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PMID:Involvement of prostaglandin F 2 alpha receptor in ATP-induced mechanical allodynia. 1949 Sep 31

Mediators of neuromuscular transmission in rat bladder strips were dissected pharmacologically to examine their susceptibilities to inhibition by botulinum neurotoxins (BoNTs) and elucidate a basis for the clinical effectiveness of BoNT/A in alleviating smooth muscle spasms associated with overactive bladder. BoNT/A, BoNT/C1, or BoNT/E reduced peak and average force of muscle contractions induced by electric field stimulation (EFS) in dose-dependent manners by acting only on neurogenic, tetrodotoxin-sensitive responses. BoNTs that cleaved vesicle-associated membrane protein proved to be much less effective. Acetylcholine (ACh) and ATP were found to provide virtually all excitatory input, because EFS-evoked contractions were abolished by the muscarinic receptor antagonist, atropine, combined with either a desensitizing agonist of P2X(1) and P2X(3) or a nonselective ATP receptor antagonist. Both transmitters were released in the innervated muscle layer and, thus, persisted after removal of urothelium. Atropine or a desensitizer of the P2X(1) or P2X(3) receptors did not alter the rate at which muscle contractions were weakened by BoNT/A. Moreover, although cholinergic and purinergic signaling could be partially delineated by using high-frequency EFS (which intensified a transient, largely atropine-resistant spike in muscle contractions that was reduced after P2X receptor desensitization), they proved equally susceptible to BoNT/A. Thus, equi-potent blockade of ATP co-released with ACh from muscle efferents probably contributes to the effectiveness of BoNT/A in treating bladder overactivity, including nonresponders to anticholinergic drugs. Because purinergic receptors are known mediators of sensory afferent excitation, inhibition of efferent ATP release by BoNT/A could also help to ameliorate acute pain and urgency sensation reported by some recipients.
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PMID:Excitatory cholinergic and purinergic signaling in bladder are equally susceptible to botulinum neurotoxin a consistent with co-release of transmitters from efferent fibers. 2057 97

Pain is a major problem after burns. Procedural pain evoked by burn dressing changes is common in patients, and its management is a critical part of treatment in acute burn injuries. Burn pain is very likely the most difficult form of acute pain to treat. ATP contributes to inflammation, and ATP is implicated in peripheral pain signaling via actions upon P2X(3) receptors. Puerarin is extracted from a traditional Chinese medicine and may act on P2X(3) receptor mechanisms. The Visual Analogue Scale (VAS) has been shown to be a sensitive indicator of pain intensity and treatment effects. Peripheral blood mononuclear cells (PBMCs) are involved in nociception or pain after burn injury. Burn patients were randomly divided into normal saline (NS) group (salt solution is saline) and puerarin-treated group and pain (Visual Analogue Scale scores) and inflammation (PBMCs) measured. Burn pain produces a stress response, so blood glucose, insulin, and cortisol levels in burn patients were determined. Furthermore, the expression of P2X(3) protein and mRNA in PBMCs was detected. The VAS scores in the puerarin-treated group were lower than those in NS group. The blood glucose, insulin, and cortisol levels in the puerarin-treated group at post-dressing changes were significantly decreased in comparison with those in NS group. The expression levels of P2X(3) protein and mRNA in PBMCs of burn patients in NS group were significantly increased in comparison with those in the puerarin-treated group. Puerarin can antagonize inflammatory factors (such as ATP) and decrease the upregulated expressions of P2X(3) protein and mRNA in PBMCs after burns to decrease VAS. Thus, puerarin had an analgesic effect on procedural pain in dressing changes of burn patients related to P2X(3) receptors.
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PMID:Puerarin alleviates burn-related procedural pain mediated by P2X(3) receptors. 3298 Sep 7