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

Deep tissue pain can be related to reduced muscle blood flow, which comprises the metabolic demand under muscle work. The tissues and receptors involved in nociception after ischaemic muscle contractions are not known. The concentration of adenosine is increased after ischaemic contractions and might act as an algesic substance. In 15 subjects, adenosine, hypertonic saline (algesic), and isotonic mannitol (placebo) were infused into the tibialis anterior muscle and compared with the pain caused by ischaemic contractions. The muscle pain intensity (visual analogue scale; VAS), distribution, and quality were assessed. Pressure pain thresholds were recorded to assess the deep tissue sensitivity. Adenosine did not induce more pain than the placebo. The maximal VAS score after hypertonic saline and ischaemic contractions was higher compared with adenosine/placebo infusions. The duration and area of pain were significantly increased after hypertonic saline infusions compared with ischaemic contractions. Higher scores on the McGill pain questionnaire were given to the "stabbing", "burning", "heavy", and "exhausting" word categories after ischaemic contractions, and "cramping" was rated higher during hypertonic saline-induced muscle pain compared with ischaemic contractions. During hypertonic saline infusions, the pressure pain threshold was decreased compared with before and immediately after the pain had vanished. The present study shows that pharmacological levels of adenosine in skeletal muscle did not induce pain. Excitation of muscle nociceptors by hypertonic saline evoked hyperalgesia, larger areas of pain, and a different quality of pain compared with ischaemic contractions, suggesting that the pain after ischaemic contractions is mediated by other populations of nociceptors in muscle and/or other tissues than excited by hypertonic saline.
Eur J Pain 2003
PMID:Experimental pain by ischaemic contractions compared with pain by intramuscular infusions of adenosine and hypertonic saline. 1252 22

Adenosine is a ubiquitous homeostatic substance released from most cells, including neurones and glia. Once in the extracellular space, adenosine modifies cell functioning by operating G-protein-coupled receptors (GPCR; A(1), A(2A), A(2B), A(3)) that can inhibit (A(1)) or enhance (A(2)) neuronal communication. Interactions between adenosine receptors and other G-protein-coupled receptors, ionotropic receptors and receptors for neurotrophins also occur, and this might contribute to a fine-tuning of neuronal function. Manipulations of adenosine receptors influence sleep and arousal, cognition and memory, neuronal damage and degeneration, as well as neuronal maturation. These actions might have therapeutic implications for neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, as well as for other neurological situations such as epilepsy, idiopathic pain or even drug addition. Peripheral side effects associated with adenosine receptor agonists limit their usefulness in therapeutics; in contrast, adenosine receptor antagonists appear to have less side effects as it is the case of the well-known non-selective antagonists theophylline (present in tea) or caffeine (abundant in coffee and tea), and their emerging beneficial actions in Parkinson's disease and Alzheimer's disease are encouraging. A(1) receptor antagonism may also be useful to enhance cognition and facilitate arousal, as well as in the periphery when deficits of neurotransmitter release occur (e.g. myasthenic syndromes). Enhancement of extracellular adenosine levels through drugs that influence its metabolism might prove useful approaches in situations such as neuropathic pain, where enhanced activation of inhibitory adenosine A(1) receptors is beneficial. One might then consider adenosine as a fine-tuning modulator of neuronal activity, which via subtle effects causes harmonic actions on neuronal activity. Whenever this homeostasis is disrupted, pathology may be installed and selective receptor antagonism or agonism required.
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PMID:Adenosine receptors in the nervous system: pathophysiological implications. 1257 92

Adenosine analogs produce analgesic actions in nociceptive paradigms and alleviate manifestations of neuropathic pain in nerve injury models in rodents. In humans, previous work indicates an analgesic effect for adenosine administered intravenously in postoperative and neuropathic pain. In this double blind placebo controlled crossover trial, we used an enriched enrolment design to determine the effects of intravenous adenosine (50 microg/kg/min over 60min) on neuropathic pain. In Phase 1 of the trial, adenosine was administered in an open label manner, while in Phase 2 adenosine was administered in a double blind placebo controlled manner to 23 adenosine responders who had experienced a 30% or greater response in the open trial. Outcome measures included the McGill pain questionnaire (MPQ), which generates a pain rating index (PRI), and contains a visual analog scale (VAS) of pain intensity, the neuropathy pain scale (NPS), and a VAS for pain relief. Subjects also graded the degree of allodynia and hyperalgesia using a VAS. Adenosine led to a significant reduction in spontaneous pain according to the MPQ-PRI, the MPQ-VAS and the VAS for pain relief. The NPS showed a pattern similar to the MPQ-PRI, with statistically significant reductions in scales 1 (intensity), 3 (hot), 6 (sensitive), 7 (itchy) and 9 (unpleasant). Adenosine also led to a significant reduction in pinprick hyperalgesia, but not in allodynia. Three patients from Phase 1 of the trial experienced long term resolution of their pain following intravenous adenosine (5,16,25 months). The results of this study support previous reports that indicate intravenous adenosine alleviates neuropathic pain and hyperalgesia.
Pain 2003 May
PMID:Intravenous adenosine alleviates neuropathic pain: a double blind placebo controlled crossover trial using an enriched enrolment design. 1274 65

In the central nervous system (CNS), adenosine is an important neuromodulator and regulates neuronal and non-neuronal cellular function (e.g. microglia) by actions on extracellular adenosine A(1), A(2A), A(2B) and A(3) receptors. Extracellular levels of adenosine are regulated by synthesis, metabolism, release and uptake of adenosine. Adenosine also regulates pain transmission in the spinal cord and in the periphery, and a number of agents can alter the extracellular availability of adenosine and subsequently modulate pain transmission, particularly by activation of adenosine A(1) receptors. The use of capsaicin (which activates receptors selectively expressed on C-fibre afferent neurons and produces neurotoxic actions in certain paradigms) allows for an interpretation of C-fibre involvement in such processes. In the spinal cord, adenosine availability/release is enhanced by depolarization (K(+), capsaicin, substance P, N-methyl-D-aspartate (NMDA)), by inhibition of metabolism or uptake (inhibitors of adenosine kinase (AK), adenosine deaminase (AD), equilibrative transporters), and by receptor-operated mechanisms (opioids, 5-hydroxytryptamine (5-HT), noradrenaline (NA)). Some of these agents release adenosine via an equilibrative transporter indicating production of adenosine inside the cell (K(+), morphine), while others release nucleotide which is converted extracellularly to adenosine by ecto-5'-nucleotidase (capsaicin, 5-HT). Release can be capsaicin-sensitive, Ca(2+)-dependent and involve G-proteins, and this suggests that within C-fibres, Ca(2+)-dependent intracellular processes regulate production and release of adenosine. In the periphery, adenosine is released from both neuronal and non-neuronal sources. Neuronal release from capsaicin-sensitive afferents is induced by glutamate and by neurogenic inflammation (capsaicin, low concentration of formalin), while that from sympathetic postganglionic neurons (probably as adenosine 5'-triphosphate (ATP) with NA) occurs following more generalized inflammation. Such release is modified differentially by inhibitors of AK and AD. Following nerve injury, there is an alteration in capsaicin-sensitive adenosine release, as spinal release now is less responsive to opioids, while peripheral release is less responsive to inhibitors of metabolism. Following inflammation, adenosine is released from a variety of cell types in addition to neurons (e.g. endothelial cells, neutrophils, mast cells, fibroblasts). ATP is released both spinally and peripherally following inflammation or injury, and may be converted to adenosine by ecto-5'-nucleotidase contributing an additional source of adenosine. Release of adenosine from both spinal and peripheral compartments has inhibitory effects on pain transmission, as methylxanthine adenosine receptor antagonists reduce analgesia produced by agents which augment extracellular levels of adenosine spinally (morphine, 5-HT, substance P, AK inhibitors) and peripherally (AK inhibitors, AD inhibitors). Increases in extracellular adenosine availability also may contribute to antiinflammatory effects of certain agents (methotrexate, sulfasalazine, salicylates, AK inhibitors), and this could have secondary effects on pain signalling in chronic inflammation. The purpose of the present review is to consider: (a). the factors that regulate the extracellular availability of adenosine in the spinal cord and at peripheral sites; and (b). the extent to which this adenosine affects pain signalling in these two distinct compartments.
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PMID:Adenosine in the spinal cord and periphery: release and regulation of pain. 1278 73

Perforated patch clamp recordings were performed on cultured superficial neonatal rat dorsal horn (DH) spinal cord neurones in order to study the presynaptic modulation of GABA release at unitary synaptic connections. Since ATP can be coreleased with GABA at about two-thirds of GABAergic synapses between DH neurones, and can be rapidly metabolized to adenosine in the extracellular space, we investigated the potential role of A1 adenosine receptors and GABAB receptors which might function as inhibitory autoreceptors. Adenosine and GABAB receptor agonists reduced the amplitude of electrically evoked GABAergic inhibitory postsynaptic currents (eIPSCs) as well as the frequency of GABAergic miniature IPSCs, suggesting a presynaptic action of these substances. The actions of adenosine were blocked by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). The effects of adenosine and GABAB agonists were occlusive, indicating a functional convergence of the signalling pathways engaged by A1 and GABAB receptors. A1 and GABAB antagonists increased the amplitude of eIPSCs in a supra-additive manner, suggesting a tonic activation of these receptors by ambient adenosine and GABA. Moreover, using trains of electrical stimulations, we were able to unravel a phasic (activity-dependent) activation of presynaptic A1 and GABAB autoreceptors only in the case of neurones coreleasing ATP and GABA, despite the presence of functional presynaptic A1 and GABAB receptors on all GABAergic DH neurones. This selective, convergent and activity-dependent inhibition of GABA release by A1 and GABAB autoreceptors might modulate the integrative properties of postsynaptic DH neurones under physiological conditions and/or during the development of pathological pain states.
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PMID:Convergent control of synaptic GABA release from rat dorsal horn neurones by adenosine and GABA autoreceptors. 1284 15

Adenosine can reduce pain and allodynia in animals and man, probably via spinal adenosine A1 receptors. In the present study, we investigate the distribution of the adenosine A1 receptor in the rat spinal cord dorsal horn using immunohistochemistry, in situ hybridization, radioligand binding, and confocal microscopy. In the lumbar cord dorsal horn, dense immunoreactivity was seen in the inner part of lamina II. This was unaltered by dorsal root section or thoracic cord hemisection. Confocal microscopy of the dorsal horn revealed close anatomical relationships but no or only minor overlap between A1 receptors and immunoreactivity for markers associated with primary afferent central endings: calcitonin gene-related peptide, or isolectin B4, or with neuronal subpopulations: mu-opioid receptor, neuronal nitric oxide synthase, met-enkephalin, parvalbumin, or protein kinase Cgamma, or with glial cells: glial fibrillary acidic protein. A few adenosine A1 receptor positive structures were double-labeled with alpha-amino-3-hydroxy-5-methyl-4-isoaxolepropionic acid glutamate receptor subunits 1 and 2/3. The results indicate that most of the adenosine A1 receptors in the dorsal horn are located in inner lamina II postsynaptic neuronal cell bodies and processes whose functional and neurochemical identity is so far unknown. Many adenosine A1 receptor positive structures are in close contact with isolectin B4 positive C-fiber primary afferents and/or postsynaptic structures containing components of importance for the modulation of nociceptive information.
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PMID:Distribution of antinociceptive adenosine A1 receptors in the spinal cord dorsal horn, and relationship to primary afferents and neuronal subpopulations. 1458 Sep 41

Adenosine is a physiological nucleoside which acts as an autocoid and activates G protein-coupled membrane receptors, designated A(1), A(2A), A(2B) and A(3). Adenosine plays an important role in many (patho)physiological conditions in the CNS as well as in peripheral organs and tissues. Adenosine receptors are present on virtually every cell. However, receptor subtype distribution and densities vary greatly. Adenosine itself is used as a therapeutic agent for the treatment of supraventricular paroxysmal tachycardia and arrhythmias and as a vasodilatatory agent in cardiac imaging. During the past 20 years, a number of selective agonists for A(1), A(2A) and A(3) adenosine receptors have been developed, all of them structurally derived from adenosine. Several such compounds are currently undergoing clinical trials for the treatment of cardiovascular diseases (A(1)and A(2A)), pain (A(1)), wound healing (A(2A)), diabetic foot ulcers (A(2A)), colorectal cancer (A(3)) and rheumatoid arthritis (A(3)). Clinical evaluation of some A(1) and A(2A) adenosine receptor agonists has been discontinued. Major problems include side effects due to the wide distribution of adenosine receptors; low brain penetration, which is important for the targeting of CNS diseases; short half-lifes of compounds; or a lack of effects, in some cases perhaps due to receptor desensitisation or to low receptor density in the targeted tissue. Partial agonists, inhibitors of adenosine metabolism (adenosine kinase and deaminase inhibitors) or allosteric activators of adenosine receptors may be advantageous for certain indications, as they may exhibit fewer side effects.
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PMID:Adenosine receptor agonists: from basic medicinal chemistry to clinical development. 1466 5

Adenosine analogues have been used by subarachnoid injection for the treatment of inflammatory and neuropathic pain. There is no data on the use of adenosine in peripheral nerve blocks. The aim of the present study was to determine the analgesic efficacy of adenosine in combination with a local anaesthetic solution for brachial plexus (BP) block. With local ethics committee approval, 50 consenting adult patients undergoing upper limb surgery were enrolled in this double-blind, prospective, randomized study. Patients with a history of bronchospastic disease were excluded. Patients were instructed not to take theophylline-containing drugs and beverages for at least one day before surgery or on the first postoperative day. A supraclavicular BP block was performed by injecting a mixture totalling 35 ml made up of prilocaine 1% 10 ml and lignocaine 2% 20 ml with adrenaline 1:200,000, and adenosine 10 mg in 5 ml saline (Group 1) or 5 ml saline (Group 2) as a placebo control group. Postoperative analgesia was assessed by time to first rescue analgesia, analgesic consumption in the first 24 hours, and VAS at rest at 4, 8, 12, 16, 20 and 24 hours. Side-effects were also noted. Vital signs were stable in both groups throughout the operation. There were no significant differences between the groups in onset of motor and sensory block. Time to first pain sensation from block was not significantly longer in the adenosine group (379 +/- 336 min) compared with controls (304 +/- 249 min, mean +/- SD, P = 0.14). Time to first analgesic requirements and analgesic consumption in the first 24 hours were also similar in both study groups. In the present study, the addition of adenosine to local anaesthetic in brachial plexus block did not significantly extend the duration of analgesia.
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PMID:Combination of adenosine with prilocaine and lignocaine for brachial plexus block does not prolong postoperative analgesia. 1471 26

Vanilloid receptor 1 (TRPV1), a nonspecific cation channel expressed primarily in small sensory neurons, mediates inflammatory thermal pain sensation. The function and expression of TRPV1 are enhanced during inflammation and certain neuropathies, leading to sustained hyperalgesia. Activation of TRPV1 in the spinal cord and periphery promotes release of adenosine, which produces analgesia by activating A(1) and A(2A) adenosine receptor (AR) on central and peripheral neurons. This study provides evidence of a direct interaction of AR analogs with TRPV1. Adenosine analogs inhibit TRPV1-mediated Ca(2+) entry in human embryonic kidney (HEK293) cells stably expressing TRPV1 (HEK/TRPV1) and DRG neurons. This inhibition was independent of A(2A)AR activation. Specific binding of [(3)H]resiniferatoxin (RTX) in plasma membrane preparations was inhibited by CGS21680, an A(2A)AR agonist. Similar degrees of inhibition were observed with both agonists and antagonists of ARs. Adenosine analogs inhibited [(3)H]RTX binding to affinity-purified TRPV1, indicative of a direct interaction of these ligands with the receptor. Furthermore, specific capsaicin-sensitive binding of [(3)H]CGS21680 was observed in Xenopus oocyte membranes expressing TRPV1. Capsaicin-induced inward currents in DRG neurons were inhibited by adenosine and agonist and antagonist of A(2A)AR at nanomolar concentrations. Increasing the concentrations of capsaicin reversed the inhibitory response to capsaicin, suggesting a competitive inhibition at TRPV1. Finally, exposure of HEK/TRPV1 cells to capsaicin induced an approximately 2.4-fold increase in proapoptotic cells that was abolished by adenosine analogs. Together, these data suggest that adenosine could serve as an endogenous inhibitor of TRPV1 activity by directly interacting with the receptor protein.
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PMID:Direct interaction of adenosine with the TRPV1 channel protein. 1507 Nov 15

Adenosine (ADO) is an endogenous inhibitory neuromodulator that increases nociceptive thresholds in response to tissue trauma and inflammation. Adenosine kinase (AK) is a key intracellular enzyme regulating intra- and extracellular concentrations of ADO. AK inhibition selectively amplifies extracellular ADO levels at cell and tissue sites where accelerated release of ADO occurs. AK inhibitors have been shown to provide effective antinociceptive, antiinflammatory and anticonvulsant activity in animal models, thus suggesting their potential therapeutic utility for pain, inflammation, epilepsy and possibly other central and peripheral nervous system diseases associated with cellular trauma and inflammation. This beneficial outcome may potentially lack nonspecific effects associated with the systemic administration of ADO receptor agonists. Until recently all of the reported AK inhibitors contained adenosine-like structural motif. The present review will discuss design, synthesis and analgesic and antiinflammatory properties of the novel nonnucleoside AK inhibitors that do not have close structural resemblance with the natural substrate ADO. Two classes of the nonnucleoside AK inhibitors are built on pyridopyrimidine and alkynylpyrimidine cores.
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PMID:Nonnucleoside inhibitors of adenosine kinase. 1507 44


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