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

At the turn of this century, it was proposed that ischemic cardiac pain might be related to distension of the ventricular wall ("mechanical hypothesis"). Three decades later, it was hypothesized that ischemic pain might be elicited by the intramyocardial release of pain-producing substances induced by ischemia ("chemical hypothesis"). Studies carried out in the past 10 years have given strong support to the chemical hypothesis, because they have consistently shown that adenosine is a mediator of ischemic cardiac pain. Adenosine-induced ischemic cardiac pain is mediated primarily by stimulation of A1 receptors located in cardiac nerve endings and is potentiated by substance P. Conversely, the magnitude and rate of left ventricular dilation during ischemia do not predict the severity of angina. It is worth noting, however, that stretching of epicardial coronary arteries appears to potentiate the severity of angina caused by myocardial ischemia. The nervous activity generated by myocardial ischemia is modulated in intrinsic cardiac, mediastinal, and thoracic ganglia. Then it is further modulated in the central nervous system and projects bilaterally to the cortex, as demonstrated in humans by positron emission tomography, where it is decoded as a painful sensation. The causes responsible for the lack of angina during myocardial ischemia are probably different in patients who present both pain-free and painful myocardial ischemia, in patients with predominantly painless ischemia, and in diabetic patients.
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PMID:New look to an old symptom: angina pectoris. 939 81

Adenosine and ATP exert multiple influences on pain transmission at peripheral and spinal sites. At peripheral nerve terminals in rodents, adenosine A1 receptor activation produces antinociception by decreasing, while adenosine A1 receptor activation produces pronociceptive or pain enhancing properties by increasing, cyclic AMP levels in the sensory nerve terminal. Adenosine A3 receptor activation produces pain behaviours due to the release of histamine and 5-hydroxytryptamine from mast cells and subsequent actions on the sensory nerve terminal. In humans, the peripheral administration of adenosine produces pain responses resembling that generated under ischemic conditions and the local release of adenosine may contribute to ischemic pain. In the spinal cord, adenosine A receptor activation produces antinociceptive properties in acute nociceptive, inflammatory and neuropathic pain tests. This is seen at doses lower than those which produce motor effects. Antinociception results from the inhibition of intrinsic neurons by an increase in K+ conductance and presynaptic inhibition of sensory nerve terminals to inhibit the release of substance P and perhaps glutamate. There are observations suggesting some involvement of spinal adenosine A2 receptors in pain processing, but no data on any adenosine A3 receptor involvement. Endogenous adenosine systems contribute to antinociceptive properties of caffeine, opioids, noradrenaline, 5-hydroxytryptamine, tricyclic antidepressants and transcutaneous electrical nerve stimulation. Purinergic systems exhibit a significant potential for development as therapeutic agents. An understanding of the contribution of adenosine to pain processing is important for understanding how caffeine produces adjuvant analgesic properties in some situations, but might interfere with the optimal benefit to be derived from others.
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PMID:Adenosine receptor activation and nociception. 965 Aug 42

Adenosine (ADO) is an endogenous modulator of intercellular signaling that provides homeostatic reductions in cell excitability during tissue stress and trauma. The inhibitory actions of ADO are mediated by interactions with specific cell-surface G-protein coupled receptors regulating membrane cation flux, polarization, and the release of excitatory neurotransmitters. ADO kinase (AK; EC 2.7.1.20) is the key intracellular enzyme regulating intra- and extracellular ADO concentrations. Inhibition of AK produces marked increases in extracellular ADO levels that are localized to cells and tissues undergoing accelerated ADO release. Thus AK inhibition represents a mechanism to selectively enhance the protective actions of ADO during tissue trauma without producing the nonspecific effects associated with the systemic administration of ADO receptor agonists. During the last 10 years, specific inhibitors of AK based on the endogenous purine nucleoside substrate, ADO, have been developed. Potent AK inhibitors have recently been synthesized that demonstrate high specificity for this enzyme as compared to other ADO metabolic enzymes, transporters, and receptors. In both in vitro and in vivo models, AK inhibitors have been shown to potently increase ADO concentrations in a tissue and event specific fashion and to demonstrate potential clinical utility in animal models of epilepsy, ischemia, pain, and inflammation. AK inhibitors have demonstrated superior efficacy in these models as compared to other mechanisms of modulating ADO availability, and these agents exhibit reduced side-effect liabilities compared to direct acting ADO receptor agonists. The preclinical profile of AK inhibitors indicate that these agents may have therapeutic utility in a variety of central and peripheral diseases associated with cellular trauma and inflammation. Clinical trials are currently underway to evaluate the efficacy of AK inhibitors in seizure disorders and pain.
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PMID:Adenosine kinase inhibitors. 1019 52

Adenosine analogs produce antinociception in normal animals and reduce allodynia and hyperalgesia following inflammation and nerve injury following spinal injection, yet none have been tested for clinical safety. While adenosine itself is in clinical trials for spinal administration, there is little data on the spinal effects of adenosine in animal models. In this study, we determined that the spinal administration of adenosine produced a dose-dependent reduction in tactile allodynia in rats following spinal nerve ligation without producing motor blockade. Although the maximal effect of adenosine was less than 50% reversal of allodynia, its duration of action was >24 h after a single spinal injection. In contrast, injection of a synthetic adenosine analog which produced an anti-allodynic action to a similar degree of effect resulted in a pronounced motor blockade. Spinal opioid action has been suggested to result in part from spinal adenosine release. We hypothesized that the reduced efficacy of spinal morphine in nerve injury-induced allodynia and hyperalgesia might reflect a disruption in this spinal opioid-adenosine mechanism. Spinal morphine itself produced a minimal reduction in allodynia in rats following spinal nerve ligation and this was enhanced in an additive manner by spinal adenosine. The maximal effect of this combination resulted in less than 60% reversal of allodynia. In contrast, spinal injection of adenosine deaminase or reuptake inhibitors greatly enhanced the effect of spinal morphine, resulting in over 80% reversal of allodynia. These results support the clinical testing of spinal adenosine alone and with morphine in the treatment of neuropathic pain, and further testing of the proposed opioid-adenosine link in normal and hyperesthetic conditions.
Pain 1999 Mar
PMID:Exogenous and endogenous adenosine enhance the spinal antiallodynic effects of morphine in a rat model of neuropathic pain. 1020 15

Adenosine (ADO) is an inhibitory neuromodulator that can increase the nociceptive threshold in animals exposed to a variety of noxious stimuli. Inhibition of the ADO-metabolizing enzyme, ADO kinase (AK), provides a means of locally enhancing extracellular ADO concentrations. In the present study, the AK inhibitors 5'-amino,5'-deoxy-ADO (NH2dADO), 5-iodotubercidin (5-IT), and 5'-deoxy,5-iodotubercidin (5'd-5IT) were examined for their analgesic efficacy in the hot-plate model of acute somatic nociception. Control and drug-treated adult male mice were placed on a 55 degrees C hot plate and the latency to the 10th jump was recorded via a computer driven infrared-beam photosensor. All three AK inhibitors were found to significantly increase jump latencies in a dose-dependent fashion. 5'd-5IT was the most potent AK inhibitor (approx. ED50 value = 1 micromol/kg, IP), followed by 5-IT (ED50 value = 10 micromol/kg, IP), and NH2dADO (ED50 value = 100 micromol/kg, IP). 5'd-5IT was found to be more potent and equally efficacious to morphine (ED50 value = 5.2 micromol/kg, IP) in this assay. In a model of persistent chemical pain, the phenyl-p-quinone-induced abdominal constriction assay, 5'd-5IT (ED50 value = 1.5 micromol/kg, SC) and morphine (ED50 value = 3.0 micromol/kg, SC) dose dependently reduced nociception. Pretreatment of mice with either the nonselective ADO receptor antagonist, theophylline (56 micromol/kg, IP), but not the peripherally acting antagonist, 8-(p-sulfophenyl)-theophylline (8-PST, 200 micromol/kg, IP) significantly attenuated the antinociceptive effects of 5'd-5IT in the hot-plate assay. Furthermore, the antinociceptive effects of 5'd-5IT were completely blocked by an ADO A1 receptor selective antagonist, DPCPX, while an ADO A2A receptor selective antagonist, ZM 241385, showed markedly less antagonist activity. The analgesic effects of 5'd-5IT were not blocked by the opioid receptor antagonist naloxone; however, 5'd-5IT could produce additive analgesic effects with morphine when both compounds were administered in combination. The apparent efficacy of 2.5 micromol/kg, IP, of 5'd-5IT was not significantly altered following the repeated administration of this dose twice daily for 4 days. The present data provide evidence for an antinociceptive action of AK inhibitors in the hot-plate test, which, at least for 5'd-5IT, is mediated by an enhancement of ADO's actions at the ADO A1 receptor subtype, is nonopioid in nature, and which does not exhibit tolerance following repeated administration.
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PMID:Characterization of the effects of adenosine kinase inhibitors on acute thermal nociception in mice. 1034 May 27

Chest pain can arise from cardiovascular or noncardiovascular causes. Among the latter are the skin, the chest wall, intrathoracic structures, or subdiaphragmatic organs. The problem to attribute the chest discomfort to either the heart or extracardiac organs arises because the heart, pleura, aorta, and esophagus are all supplied by sensory fibers from the same spinal segments. In contrast to the diseases mentioned above, angina pectoris in sensu strictu is defined as chest pain or discomfort of cardiac origin that arises because of temporary imbalance between myocardial oxygen supply and demand. The metabolic oxygen requirements of the myocardium are essentially dictated by myocardial contraction since only a fraction of the consumed oxygen is needed by the quiescent heart. Therefore, the factors that primarily influence myocardial oxygen consumption include heart rate, the force of cardiac contraction, and myocardial wall tension, as determined by pressure (afterload), volume (preload), and wall thickness. Extracoronary diseases, e.g. hypertensive heart disease, aortic stenosis or cardiomyopathies, can influence these factors and induce angina pectoris (Figure 1). On the other hand, different diseases influencing the oxygen supply, e.g. anemia, can cause angina pectoris, too. In addition, the modulation of the coronary tone by mediators and cytokines can cause angina, coronary spasm being one example. The neurophysiological substrate of angina pectoris are ganglia which are present within the heart, particularly in epicardial fat. The sympathetic nervous system is the main conveyer of afferent pain fibers from the heart and pericardium, but many fibers may travel by the vagus and the phrenic nerves. Therefore, multiple thoracic structures may cause similar pain syndromes in the distressed patient. The blood supply of intrinsic cardiac ganglia arises primarily from branches of the proximal coronary arteries. Adenosine, among a number of substances, can modulate the activity generated by cardiac afferent nerve endings and intrinsic cardiac neurones. During myocardial ischemia adenosine is released in large quantities into the interstitial space. Given as an intravenous bolus to healthy volunteers or to patients with ischemic heart disease and angina pectoris, adenosine provokes angina pectoris-like pain, which is similar to habitual angina pectoris with regard to quality and location. But other mediators (e.g. bradykinin, histamine, prostaglandins, potassium, lactate) can be involved in the development of angina pectoris, too. As most emphasis should be given to the most serious causes first, the cardiologist has to consider ischemic cardiac disease in the differential diagnosis of nearly every case of acute chest pain. The differential diagnosis contains several causes of nonischemic cardiac chest pain. Dissecting aortic aneurysm may cause severe anterior chest pain that can be mistaken for myocardial infarction. Patients frequently will note the sudden onset of the pain rather than the relatively slower onset of ischemic pain. Furthermore, they feel as a tear and describe it as the most severe pain they have ever had. Pericarditis can be characterized as a sharp precordial knife-like pain that is often increased by lying down, breathing, swallowing, or any other thoracic motion. Radiation of pericardial pain is often relieved by sitting up or leaning forward. It may involve the shoulders, upper back, and neck because of the irritation of the diaphragmatic pleura. Acute pulmonary embolism is associated with severe chest pain. It may mimic acute myocardial infarction. Pulmonary embolism should be suspected when dyspnea or tachypnea seems to be disproportionate to the severity of the chest pain. Diffuse esophageal spasm is the extracardiac condition that is confused most often with ischemic cardiac chest pain. This pain presents as a deep thoracic pain that may be present over most of the thorax. It may extend down the anterome
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PMID:[Angina pectoris in extracoronary diseases]. 1037 99

Adenosine 5'-triphosphate (ATP) is a purine nucleotide found in every cell of the human body. In addition to its well established role in cellular metabolism, extracellular ATP and its breakdown product adenosine, exert pronounced effects in a variety of biological processes including neurotransmission, muscle contraction, cardiac function, platelet function, vasodilatation and liver glycogen metabolism. These effects are mediated by both P1 and P2 receptors. A cascade of ectonucleotidases plays a role in the effective regulation of these processes and may also have a protective function by keeping extracellular ATP and adenosine levels within physiological limits. In recent years several clinical applications of ATP and adenosine have been reported. In anaesthesia, low dose adenosine reduced neuropathic pain, hyperalgesia and ischaemic pain to a similar degree as morphine or ketamine. Postoperative opioid use was reduced. During surgery, ATP and adenosine have been used to induce hypotension. In patients with haemorrhagic shock, increased survival was observed after ATP treatment. In cardiology, ATP has been shown to be a well tolerated and effective pulmonary vasodilator in patients with pulmonary hypertension. Bolus injections of ATP and adenosine are useful in the diagnosis and treatment of paroxysmal supraventricular tachycardias. Adenosine also allowed highly accurate diagnosis of coronary artery disease. In pulmonology, nucleotides in combination with a sodium channel blocker improved mucociliary clearance from the airways to near normal in patients with cystic fibrosis. In oncology, there are indications that ATP may inhibit weight loss and tumour growth in patients with advanced lung cancer. There are also indications of potentiating effects of cytostatics and protective effects against radiation tissue damage. Further controlled clinical trials are warranted to determine the full beneficial potential of ATP, adenosine and uridine 5'-triphosphate.
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PMID:Adenosine triphosphate: established and potential clinical applications. 1047 17

Recent studies indicate a widening role for adenosine receptors in many therapeutic areas. Adenosine receptors are involved in immunological and inflammatory responses, respiratory regulation, the cardiovascular system, the kidney, various CNS-mediated events including sleep and neuroprotection, as well as central and peripheral pain processes. In this review, the physiological role of adenosine receptors in these key areas is described with reference to the therapeutic potential of adenosine receptor agonists and antagonists.
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PMID:Adenosine receptors as potential therapeutic targets. 1055 36

It has been proposed that adenosine mediates ischaemic pain in humans. Patients with cardiac Syndrome X are hypersensitive to potential pain stimuli, including adenosine. On the other hand, recent findings suggest that low-dose adenosine infusion may have analgesic effects. Our aim was to test two hypotheses: (1) that the analgesic effect of adenosine is peripheral in origin, and (2) that part of the hypersensitivity to pain of patients with cardiac Syndrome X results from a disturbed mechanism of adenosine analgesia. A total of 12 female Syndrome X patients and eight healthy age-matched female controls were studied in a randomized, double-blind and placebo-controlled study. Adenosine (70 microg/min) or placebo was infused into the forearm via an intra-arterial catheter. After 15 min of infusion, a tourniquet on the upper arm was inflated to 225 mmHg to ensure arterial occlusion. The patient then carried out dynamic handgrip work at 60 Hz. Pain or discomfort in the forearm was estimated continuously according to the Borg CR-10 scale. After the first test, theophylline was infused for 10 min intravenously at a dose of 5 mg/kg body weight. The ischaemic forearm test was then repeated. On a second occasion, the procedure was repeated with the opposite treatment (adenosine/placebo). Only six of 12 Syndrome X patients completed the protocol because of pain during the catheterization procedure or an inability to establish an intra-arterial line. The time to onset of pain in the working, ischaemic forearm was greater for subjects treated with adenosine than for those treated with placebo, both in those Syndrome X patients who tolerated catheterization (49+/-27 s compared with 32+/-18 s; P<0.03) and in healthy controls (40+/-19 s compared with 16+/-8 s; P<0.02). The time to maximum pain, limiting ischaemic work, was also greater with adenosine pretreatment both in Syndrome X patients (137+/-28 s compared with 106+/-28 s; P<0.03) and in healthy controls (109+/-31 compared with 82+/-18 s; P<0.01). After infusion of theophylline there was no difference between adenosine and placebo in either group. Intra-arterially infused adenosine had similar peripheral analgesic effects on experimentally induced muscular ischaemia in those female Syndrome X patients who tolerated intra-arterial catheterization and in healthy controls. Thus adenosine analgesia is counteracted by theophylline, suggesting that the effect is mediated by membrane-bound peripheral adenosine receptors.
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PMID:Analgesic effects of adenosine in syndrome X are counteracted by theophylline: a double-blind placebo-controlled study. 1060 Jun 54

Although significant improvement has been made in the treatment of pain in the postoperative period, many patients still experience unnecessary discomfort resulting in distress, higher morbidity and prolonged stay in hospital. The standard pillar of postoperative treatment of severe pain is the use of opioids. However, adverse reactions to opioids make their use unfavourable. A better understanding of the pathophysiology of pain has helped clinicians to a more balanced approach to postoperative pain treatment. The development of the multimodal approach to postoperative analgesia, with the use of different drugs acting via different routes to give good analgesia, with minimal side-effects, represents a major development in the treatment of postoperative pain. Early, aggressive mobilisation and feeding must follow in order to restore normal conditions quickly. Alternatives to opioids should be used as extensively as possible. Local anaesthesia, used as regional blocks or as wound infiltration, is most beneficial. Paracetamol has good basic analgesic properties, and should probably be used in dosages higher than recommended today. The combination with a NSAID results in better and longer-lasting analgesia. The intravenous form propacetamol will increase the possibilities of its use. The new concept of selective COX-2 inhibiting NSAIDs will result in analgesic and anti-inflammatory drugs with fewer side-effects. The well-known inexpensive group of corticosteroids have good analgesic and anti-emetic properties, and are especially interesting to use in patients who do not tolerate NSAIDs. The alpha2-receptor agonists like clonidine, when administered epidurally or intrathecally, are useful adjuncts, but their adverse effects on sedation and hypotension limit their use. NMDA-receptor antagonists are of limited value in the postoperative period. Adenosine and neostigimine are still on a research level but may lead to new, clinically useful analgesic drugs. In the future, cannabinoids, cholecystokinin-receptor antagonists and neurokinin-1 antagonists may become important analgesic drugs.
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PMID:Non-opioid postoperative analgesia. 1106 98


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