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 the last two decades, considerable advances have been made in our understanding of the mechanisms of pain. Studies correlating subjective magnitude estimations of pain in man with activity in single nerve fibers in experimental animals, and microneurographic recordings in awake humans, have provided convincing evidence for the role of specific nociceptors and labelled lines for signalling pain sensation in the normal skin. The response properties of the different types of nociceptive afferents, both myelinated and unmyelinated, from skin, muscle, and joints make them ideal candidates for signalling pain sensations. Cutaneous inflammation from any cause results in hyperalgesia. Cutaneous hyperalgesia at the site of an injury, i.e., primary hyperalgesia, can be explained by sensitization of nociceptors. This sensitization is likely due to local release of chemical mediators in the inflamed area. The metabolites of arachidonic acid (eicasonoids) and bradykinin appear to play an important role in the sensitization of nociceptors. Similar inflammation-induced changes in response properties of fine articular afferents might explain the pain of acute arthritis. The neuropeptide substance P released from primary afferents may also play an important role in the pathogenesis of arthritis. The mechanism of hyperalgesia in the region surrounding the injury, i.e., secondary hyperalgesia, is less well understood, and probably results from changes both in the peripheral and central nervous systems. While considerable advances have been made in our understanding of the mechanisms of acute pain, the pathophysiology of most chronic pain states is still unclear. We hope that future studies in experimental animals, and careful psychophysical testing and microneurographic recordings in chronic pain patients, will lead to a better understanding of the pathophysiology of pain.
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PMID:Peripheral mechanisms of somatic pain. 328 12

There must be a differentiation between acute and chronic pain. While acute pain should be treated causally, this is usually no longer possible when pain has become chronic. It may even become so intense that a chronic pain patient can no longer live a productive life. The pain threshold is decreased by endogenous substances like prostaglandin E, but also kallekrein and bradykinin. Hyperadrenergic stimuli can advance pain; for example, the so-called phantom-limb pain. Also important within the biorhythm is the time of day, the physical state of activity and the psychological constitution. The pain patient often uses his disease to focus the attention of the physician on him. There are central and peripheral acting analgesics available for treatment of pain. The effect of peripheral acting analgesics can be explained by inhibition of the prostaglandin synthesis, by ASS (ASA) and its descendants, the antirheumatic agents. These acidic substances are mainly concentrated in the inflammatory tissue. They act as antiphlogistics, analgetics, and antipyretics. Descendants of phenacetin act as analgetics and antipyretics. Efficacy usually lasts 3 hours. Therefore these substances should be administered regularly and in sufficient doses, according to a fixed daily schedule. This reduces unnecessary pain and avoids overdosages. To reduce side effects and tachyphylaxis, a change of analgesics in intervals of approx. 6 weeks proved satisfactory. If peripheral analgesics are no longer sufficient, for example in the final phase of a carcinoma disease, morphine and its derivatives will then be applied. To reduce the dosage, additionally a neuroleptic drug and eventually a thymoleptic drug may be administered.
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PMID:[Pain and its management with drugs]. 716 35

A number of plant species used in traditional medicine for the relief of pain have been selected from the medicinal and scientific literature of China, South America, Asia and West Africa. Extracts were prepared and tested in three in vitro receptor radioligand binding assays to determine whether there was an indication of biological activity, in particular their selectivity to a single receptor implicated in the mediation of pain. The three neuropeptide receptors chosen were Bradykinin (BK II), expressed in Chinese hamster ovary cells (CHO), neurokinin 1 (NK 1) expressed in astrocytoma cells, and calcitonin gene related peptide (CGRP) which were all implicated in the mediation of acute pain in the mammaliancentral nervous system. The plant species chosen to investigate were Ageratum conyzoides, Barringtonia edulis, Croton tiglium, Ipomea pes-caprae, Panax ginseng, Physostigma venenosum, Sinomenium acutum, Solidago virgaurea, Symplocos leptophylla and Typhonium giganteum. The results showed that there was a strong indication of biological activity for some of the plants which are used ethnomedicinally to treat pain, in the three in vitro receptor binding assays used, and particular plant extracts exhibited selective action to a single receptor.
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PMID:Ethnomedicinally selected plants as sources of potential analgesic compounds: indication of in vitro biological activity in receptor binding assays. 1064 Oct 43

A renewed interest in the characteristics and neural basis of corneal and conjunctival sensations is developing in recent years due to the high incidence of discomfort and altered sensitivity of the cornea following refractive surgery, use of contact lenses and dry eyes. Corneal nerves are functionally heterogeneous: about 20% respond exclusively to noxious mechanical forces (mechano-nociceptors); 70% are additionally excited by extreme temperatures, exogenous irritant chemicals and endogenous inflammatory mediators (polymodal nociceptors), and 10% are cold-sensitive and increase their discharge with moderate cooling of the cornea (cold receptors). Each of these types of sensory fibres contributes distinctly to corneal sensations. Mechano-nociceptors mediate, sharp acute pain produced by touching of the cornea. Polymodal nociceptors elicit the sustained irritation and pain that accompany corneal wounding; cold receptors evoke cooling sensations. Depending on the relative activation by the stimulus of each subpopulation of corneal sensory fibres, different subqualities of irritation and pain sensations are evoked. Corneal sensations can be explored experimentally in humans with a gas esthesiometer that applies controlled mechanical, chemical and thermal stimuli to the corneal surface. When the cornea is wounded, corneal nerves are excited and eventually severed in a variable degree and local inflammation is produced. Activated corneal nerves release neuropeptides (SP, CGRP) that contribute to the inflammatory reaction (neurogenic inflammation). They also become sensitized by local inflammatory mediators, such as prostaglandins or bradykinin and thus exhibit spontaneous activity, lowered threshold and enhanced responses to new stimuli. This leads to spontaneous pain and hyperalgesia. Nerves destroyed by injury soon start to regenerate and form microneuromas that exhibit abnormal responsiveness and spontaneous discharges, due to an altered expression of ion channel proteins in the soma and in regenerating nerve terminals. Presumably, this altered excitability is the origin of the lowered sensitivity and the spontaneous pain, dry eye sensations and other disaesthesias reported in patients following refractive surgery.
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PMID:Neural basis of sensation in intact and injured corneas. 1510 30

Glutamate may be released from muscle nociceptors and thereby contribute to mechanisms underlying acute and chronic muscle pain. In vivo concentration of glutamate during muscle pain has not previously been studied in either animals or humans. In the present study, we aimed to study the in vivo concentration of glutamate before, during and after acute pain of trapezius muscle in humans using the microdialysis technique. In addition, we examined the nutritive skeletal muscle blood flow and the interstitial concentrations of lactate, glucose, glycerol, pyruvate and urea. Experimental pain and tenderness were induced by intramuscular infusion of a chemical mixture consisting of bradykinin, prostaglandin E(2), histamine and serotonin. One EMG-needle and one microdialysis catheter were inserted into non-dominant and dominant trapezius muscles on a standard anatomical point in 19 healthy subjects. Dialysates were collected at rest, during infusion and 60 and 120 min after stop of infusion. Local tenderness was recorded at baseline and at the end of experiment. Local pain was recorded during infusion. The infusion of chemical mixture was more painful than infusion of placebo (p < 0.05) and resulted in significantly higher local tenderness score than placebo (p = 0.007). There was no difference in change in interstitial concentrations of glutamate, lactate, glucose, glycerol, pyruvate and urea from baseline to infusion and post-infusion periods between chemical mixture and placebo (p > 0.05). Muscle blood flow increased significantly over time in response to infusion of chemical mixture and placebo (p = 0.001). However, we found no difference in changes in muscle blood flow between chemical mixture and placebo (p > 0.05). In conclusion, the present study demonstrates no signs of increased release of glutamate from myofascial nociceptors during and after acute experimentally induced muscle pain and tenderness.
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PMID:No release of interstitial glutamate in experimental human model of muscle pain. 1586 83

Transient receptor potential (TRP) channels detect diverse sensory stimuli, including alterations in osmolarity. However, a molecular detector of noxious hypertonic stimuli has not yet been identified. We show here that acute pain-related behavior evoked by elevated ionic strength is abolished in TRP vanilloid subtype 1 (TRPV1)-null mice and inhibited by iodoresiniferatoxin, a potent TRPV1 antagonist. Electrophysiological recordings demonstrate a novel form of ion channel modulation by which extracellular Na+, Mg2+, and Ca2+ ions sensitize and activate the capsaicin receptor, TRPV1. At room temperature, increasing extracellular Mg2+ (from 1 to 5 mM) or Na+ (+50 mM) increased ligand-activated currents up to fourfold, and 10 mM Mg2+ reduced the EC50 for activation by capsaicin from 890 to 450 nM. Moreover, concentrations of divalent cations >10 mM directly gate the receptor. These effects occur via electrostatic interactions with two glutamates (E600 and E648) formerly identified as proton-binding residues. Furthermore, phospholipase C-mediated signaling enhances the effects of cations, and physiological concentrations of cations contribute to the bradykinin-evoked activation of TRPV1 and the sensitization of the receptor to heat. Thus, the modulation of TRPV1 by cationic strength may contribute to inflammatory pain signaling.
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PMID:Extracellular cations sensitize and gate capsaicin receptor TRPV1 modulating pain signaling. 1591 51

Many known painkillers are not always effective in the therapy of chronic neuropathic pain manifested by hyperalgesia and tactile allodynia. The mechanisms underlying neuropathic pain appear to be complicated and to differ from acute and inflammatory pain. Recent advances in pain research provide us with a clear picture for the molecular mechanisms of acute pain, and substantial information is available concerning the plasticity that occurs under conditions of neuropathic pain. The most important changes responsible for the mechanisms of neuropathic pain are found in the altered gene/protein expression in primary sensory neurons. After damage to peripheral sensory fibers, up-regulated expression of the Ca(v)alpha(2)delta-(1) channel subunit, the Na(v)1.3 sodium channel, and bradykinin (BK) B1 and capsaicin TRPV1 receptors in myelinated neurons contribute to hyperalgesia; while the down-regulation of the Na(v)1.8 sodium channel, B2 receptor, substance P (SP), and even mu-opioid receptors in unmyelinated neurons is responsible for the phenotypic switch in pain transmission. Clarification of the molecular mechanisms for such complicated plasticity would be extremely valuable when considering the therapeutic design of pain relieving drugs. Although many reports deal with the changes in expression of key molecules related to neuropathic pain, the initiation and the mechanisms that follow remain to be determined. The current study using lysophosphatidic acid (LPA) receptor knockout mice revealed that LPA produced by nerve injury initiates neuropathic pain and demyelination following partial sciatic nerve ligation (PSNL). A single injection of LPA was found to mimic PSNL in terms of neuropathic pain and its underlying mechanisms. This discovery may lead to the subsequent discovery of LPA-induced secondary genes, which would be therapeutic targets for neuropathic pain.
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PMID:Molecular mechanisms of neuropathic pain-phenotypic switch and initiation mechanisms. 1602 29

Bradykinin produced at sites of tissue injury and inflammation elicits acute pain and alters the sensitivity of nociceptive neurons to subsequent stimuli. We tested the hypothesis that bradykinin could elicit long-lasting changes in nociceptor function by activating members of the nuclear factor of activated T-cells (NFAT) family of transcription factors. Bradykinin activation of B2 receptors evoked concentration-dependent (EC50 = 6.0 +/- 0.3 nM) increases in intracellular Ca2+ concentration ([Ca2+]i) in a proportion of dorsal root ganglion neurons in primary culture. These [Ca2+] increases were sensitive to inhibition of phospholipase C (PLC) and depletion of Ca2+ stores. In neurons expressing a green fluorescent protein (GFP)-NFAT4 fusion protein, a 2-min exposure to bradykinin induced the translocation of GFP-NFAT4 from the cytoplasm to the nucleus. Translocation was partially inhibited by the removal of extracellular Ca2+ and was blocked by inhibition of calcineurin. Furthermore, bradykinin triggered a concentration-dependent increase in NFAT-mediated transcription of a luciferase gene reporter (EC50 = 24.2 +/- 0.1 nM). This depended on the B2 receptor, PLC activation, and inositol triphosphate-mediated Ca2+ release. Transcription was not inhibited by capsazepine. Finally, as indicated by quantitative reverse transcription-polymerase chain reaction, bradykinin elicited an increase in cyclooxygenase mRNA. This increase was sensitive to calcineurin and B2 receptor inhibition. These findings suggest a mechanism by which short-lived bradykinin-mediated stimuli can enact lasting changes in nociceptor function and sensitivity.
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PMID:Bradykinin-induced nuclear factor of activated T-cells-dependent transcription in rat dorsal root ganglion neurons. 1748 65

Altered function of Na+ channels is responsible for increased hyperexcitability of primary afferent neurons that may underlie pathological pain states. Recent evidence suggests that the Nav1.9 subunit is implicated in inflammatory but not acute pain. However, the contribution of Nav1.9 channels to the cellular events underlying nociceptor hyperexcitability is still unknown, and there remains much uncertainty as to the biophysical properties of Nav1.9 current and its modulation by inflammatory mediators. Here, we use gene targeting strategy and computer modeling to identify Nav1.9 channel current signature and its impact on nociceptors' firing patterns. Recordings using internal fluoride in small DRG neurons from wild-type and Nav1.9-null mutant mice demonstrated that Nav1.9 subunits carry the TTX-resistant "persistent" Na+ current called NaN. Nav1.9(-/-) nociceptors showed no significant change in the properties of the slowly inactivating TTX-resistant SNS/Nav1.8 current. The loss in Nav1.9-mediated Na+ currents was associated with the inability of small DRG neurons to generate a large variety of electrophysiological behaviors, including subthreshold regenerative depolarizations, plateau potentials, active hyperpolarizing responses, oscillatory bursting discharges, and bistable membrane behaviors. We further investigated, using CsCl- and KCl-based pipette solutions, whether G-protein signaling pathways and inflammatory mediators upregulate the NaN/Nav1.9 current. Bradykinin, ATP, histamine, prostaglandin-E2, and norepinephrine, applied separately at maximal concentrations, all failed to modulate the Nav1.9 current. However, when applied conjointly as a soup of inflammatory mediators they rapidly potentiated Nav1.9 channel activity, generating subthreshold amplification and increased excitability. We conclude that Nav1.9 channel, the molecular correlate of the NaN current, is potentiated by the concerted action of inflammatory mediators that may contribute to nociceptors' hyperexcitability during peripheral inflammation.
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PMID:Inflammatory mediators increase Nav1.9 current and excitability in nociceptors through a coincident detection mechanism. 1827 Jan 72

Bradykinin is the most potent endogenous inducer of acute pain. However, the way in which it excites nociceptive sensory nerve endings is still unclear. In an article recently published in the JCI, Liu et al. suggest a new mechanism via which bradykinin induces acute spontaneous pain. The authors report that the stimulation of B2 bradykinin receptors by bradykinin triggers the release of intracellular calcium ions from nociceptive sensory neurons of rat dorsal root ganglia. This depolarizes the sensory nerve endings by simultaneously closing M-type potassium channels and opening TMEM16A chloride channels, resulting in the production of nociceptive signals. Here, we discuss the relationship between this effect and a previously described mechanism for pain sensitization and evaluate its potential significance for therapeutic pain control. A separate study by Patwardhan et al. in this issue of the JCI identifies oxidized linoleic acid metabolites as novel mediators of thermally induced pain.
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PMID:Some new insights into the molecular mechanisms of pain perception. 2042 17


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