Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine A1 receptor agonists are effective antinociceptive agents in neuropathic and inflammatory pain, though they appear to be weak analgesics in acute nociception. Important discrepancies are observed on the effectiveness and potency of adenosine analogues when comparing different studies, probably due to the use of different ligands, models of antinociception, routes of administration and types of sensitization. We studied the systemic antinociceptive effects of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) in spinal cord neuronal responses from adult male rats in acute nociception and in sensitization due to arthritis and neuropathy. The experiments showed that CPA was effective in the three experimental conditions, with a similar potency in reducing responses to noxious mechanical stimulation (ID50s: 20 +/- 1.2 microg/kg in acute nociception, 18 +/- 1.1 microg/kg in arthritis, 17.4 +/- 2 microg/kg in neuropathy). The phenomenon of wind-up was also dose-dependently reduced by CPA in the three experimental situations although the main action was seen in arthritis. Depression of blood pressure by CPA was not dose-dependent. We conclude that systemic CPA is a potent and effective analgesic in sensitization due to arthritis and neuropathy but also in acute nociception. The effect is independent of the cardiovascular activity and is centrally mediated since wind-up was inhibited.
 ...
PMID:The antinociceptive effects of the systemic adenosine A1 receptor agonist CPA in the absence and in the presence of spinal cord sensitization. 1640 70

Adenosine receptors belong to the family of G protein-coupled receptors. Four distinct subtypes are known, termed A(1), A(2A), A(2B) and A(3). Adenosine is an important signaling molecule which is released under inflammatory conditions. It can show antiinflammatory as well as proinflammatory activities, and the contribution of the specific adenosine receptor subtypes in various cells, tissues and organs is complex. Agonists selective for adenosine A(1) receptors show antinociceptive activity and are active in animal models of neuropathic and inflammatory pain. Adenosine A(2A) receptor agonists are potent antiinflammatory drugs. A(2A)-selective antagonists have shown antihyperalgesic activity in animal models of inflammatory pain. For A(2B)agonists as well as A(2B) antagonists antiinflammatory activity has been postulated. Selective A(2B) antagonists were shown to decrease (inflammatory) pain, and are promising candidates for the treatment of asthma. Adenosine A(3) receptor agonists appear to be proinflammatory, while there is evidence for an antiinflammatory effect of A(3) antagonists. There are some contradictory findings, and A(3) agonists are being developed for the treatment of inflammatory diseases such as arthritis. Indirect mechanisms increasing the extracellular concentration of adenosine using adenosine kinase inhibitors, adenosine deaminase inhibitors or adenosine uptake inhibitors, or increasing the potency of adenosine at the A(1) receptor subtype by allosteric modulators lead to potent antinociceptive and antiinflammatory activity. The advantage of indirectly acting drugs may be their site- and event-specific action since they are only active where adenosine has been released. In the past decade considerable progress has been made towards the identification of novel lead structures and the development of potent and selective ligands for all four adenosine receptor subtypes. A large number of patents has recently been filed and the field is finally in the process of translating many years of basic science into therapeutic application. This review article will focus on compounds published or patented within the past three years.
 ...
PMID:Recent progress in the development of adenosine receptor ligands as antiinflammatory drugs. 1691 56

Adenosine and ATP, via P1 and P2 receptors respectively, can modulate pain transmission under physiological, inflammatory, and neuropathic pain conditions. Such influences reflect peripheral and central actions and effects on neurons as well as other cell types. In general, adenosine A1 receptors produce inhibitory effects on pain in a number of preclinical models and are a focus of attention. In humans, i.v. infusions of adenosine reduce some aspects of neuropathic pain and can reduce postoperative pain. For P2X receptors, there is a significant body of information indicating that inhibition of P2X3 receptors may be useful for relieving inflammatory and neuropathic pain. More recently, data have begun to emerge implicating P2X4, P2X7 and P2Y receptors in aspects of pain transmission. Both P1 and P2 receptors may represent novel targets for pain relief.
 ...
PMID:Adenosine and ATP receptors. 1708 28

Adenosine is a neuromodulator with complex effects on pain pathways. Mice lacking the adenosine A2A receptor are hypoalgesic, and have altered analgesic responses to receptor-selective opioid agonists. These and other findings suggest a role for the adenosine A2A receptor in sensitizing afferent fibres projecting to the spinal cord. To test this hypothesis formalin (20 microl, 5%) was injected into the paw and nociceptive responses were measured in wildtype and adenosine A2A receptor knockout mice. There was a significant reduction in nociception associated with sensory nerve activation in the knockout mice as measured by time spent biting/licking the formalin-injected paw and number of flinches seen during the first phase, but only the number of flinches was reduced during the second inflammatory phase. In addition, the selective adenosine A2A antagonist SCH58261 (3 and 10 mg/kg) also antagonised both phases of the formalin test. We also labelled NMDA glutamate and NK1 receptors in spinal cord sections as an indirect measure of nociceptive transmission from peripheral sites to the spinal cord. [3H]-Substance P binding to NK1 receptors was unaltered but there was a substantial reduction in binding of [3H]-MK801 to NMDA glutamate receptors in all regions of the spinal cord from knockout mice. The decrease in NMDA glutamate receptor binding may reflect reduced peripheral sensory input to the spinal cord during development and could relate to the hypoalgesia in this genotype. These results support a key role for the adenosine A2A receptor in peripheral nociceptive pathways.
Pain 2007 Jun
PMID:Reduced response to the formalin test and lowered spinal NMDA glutamate receptor binding in adenosine A2A receptor knockout mice. 1713 34

Treating ischemic pain is often unsatisfactory. Current findings demonstrate that patients with chronic ischemia may develop sensory neuropathy and signs of central sensitization. This issue makes is reasonable treating with conventional analgesics and drugs against neuropathic pain. Adenosine has also a pain reducing effect in neuropathic pain which makes it a possible therapeutic option in ischemic pain.We report of a patient with thromboangiitis obliterans. We treated his pain with a broad analgesic therapy and administered adenosine intravenously, which resulted in a reduction of pain for several hours. Afterwards the patient received buflomedil to increase adenosine plasma levels. A long term pain reduction could be achieved. Modulation of adenosine demonstrates an experimental approach in the therapy of ischemic pain in thromboangiitis obliterans.
 ...
PMID:[Adenosine for treatment of ischemic pain in thromboangiitis obliterans. A case report]. 1726 13

Adenosine A2A receptors localized in the dorsal striatum are considered as a new target for the development of antiparkinsonian drugs. Co-administration of A2A receptor antagonists has shown a significant improvement of the effects of l-DOPA. The present review emphasizes the possible application of A2A receptor antagonists in pathological conditions other than parkinsonism, including drug addiction, sleep disorders and pain. In addition to the dorsal striatum, the ventral striatum (nucleus accumbens) contains a high density of A2A receptors, which presynaptically and postsynaptically regulate glutamatergic transmission in the cortical glutamatergic projections to the nucleus accumbens. It is currently believed that molecular adaptations of the cortico-accumbens glutamatergic synapses are involved in compulsive drug seeking and relapse. Here we review recent experimental evidence suggesting that A2A antagonists could become new therapeutic agents for drug addiction. Morphological and functional studies have identified lower levels of A2A receptors in brain areas other than the striatum, such as the ventrolateral preoptic area of the hypothalamus, where adenosine plays an important role in sleep regulation. Although initially believed to be mostly dependent on A1 receptors, here we review recent studies that demonstrate that the somnogenic effects of adenosine are largely mediated by hypothalamic A2A receptors. A2A)receptor antagonists could therefore be considered as a possible treatment for narcolepsy and other sleep-related disorders. Finally, nociception is another adenosine-regulated neural function previously thought to mostly involve A1 receptors. Although there is some conflicting literature on the effects of agonists and antagonists, which may partly be due to the lack of selectivity of available drugs, the studies in A2A receptor knockout mice suggest that A2A receptor antagonists might have some therapeutic potential in pain states, in particular where high intensity stimuli are prevalent.
 ...
PMID:Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry implications for drug addiction, sleep and pain. 1753 11

Adenosine, a ubiquitous metabolic intermediate in the body, is involved in nearly every aspect of cell function, including neuromodulation and neurotransmission. Adenosine A(1) and A(2) receptors are widely distributed in the brain and spinal cord, and are a novel, non-opiate target for pain management. The potential of adenosine as a non-narcotic analgesic in anesthetized patients has been explored in clinical trials, including double-blind studies versus placebo and remifentanil infusion. These studies suggest that, compared to placebo or remifentanil, an intraoperative adenosine infusion stabilizes core hemodynamics and reduces the requirement for anesthesia during surgery. Further, adenosine improves postoperative recovery, as indicated by lower pain scores and less opioid consumption. The safety profile of adenosine has been well characterized based on use of currently approved adenosine products. The most common adverse events associated with its use include flushing, chest discomfort, dyspnea, headache, gastrointestinal discomfort, and lightheadedness. These effects are generally well tolerated and transient. Further studies are warranted to investigate the full potential of adenosine as a non-opioid analgesic in the perioperative setting.
 ...
PMID:Adenosine as a non-opioid analgesic in the perioperative setting. 1764 10

Adenosine receptors (ARs) are a four-member subfamily of G protein-coupled receptors and are major targets of caffeine and theophylline. There are four subtypes of ARs, designated as A1, A2A, A2B and A3. Selective agonists are now available for all four subtypes. Over a dozen of these selective agonists are now in clinical trials for various conditions, although none has received regulatory approval except for the endogenous AR agonist adenosine itself. A1AR agonists are in clinical trials for cardiac arrhythmias and neuropathic pain. A2AAR agonists are now in trials for myocardial perfusion imaging and as anti-inflammatory agents. A2BAR agonists are under preclinical scrutiny for potential treatment of cardiac ischemia. A3AR agonists are in clinical trials for the treatment of rheumatoid arthritis and colorectal cancer. The present review will mainly cover the agonists that are presently in clinical trials for various conditions and only a brief introduction will be given to major chemical classes of AR agonists presently under investigation.
 ...
PMID:Emerging adenosine receptor agonists. 1787 74

The involvement of adenosinergic pathway in the anti-nociceptive effect of duloxetine, a balanced 5-HT/NE reuptake inhibitor, was evaluated in streptozotocin induced diabetic male albino mice of Laca strain. After four weeks of single injection of streptozotocin (200 mg/kg, ip), mice were tested in the tail immersion and hot-plate assays. Cerebral adenosine levels were measured by high-performance liquid chromatography (HPLC/PDA detector). Diabetic mice exhibited significant hyperalgesia along with increased plasma glucose, decreased body weights and reduced cerebral adenosine levels. Administration of duloxetine (5, 10 and 20 mg/kg, ip) to diabetic mice produced dose-dependent anti-nociceptive effect in both tail-immersion and hot-plate assays. Adenosine levels were also significantly and dose-dependently increased by different doses of duloxetine. The results demonstrated the involvement of adenosinergic pathway in duloxetine mediated anti-hyperalgesia in diabetic neuropathic pain.
 ...
PMID:Anti-nociceptive effect of duloxetine in mouse model of diabetic neuropathic pain. 1940 85

Diabetic neuropathic pain is generally considered to be one of the most troublesome complications affecting diabetic patients and current therapy provides inadequate pain relief. In the present study, the effect of adenosine was investigated in a model of diabetic neuropathic pain. Diabetes was induced by streptozotocin (65 mg/kg, ip) in male Sprague Dawley rats and subjected to thermal (cold and hot) and chemical (formalin) stimuli. Diabetic rats developed hyperalgesia by the end of six weeks in thermal and chemical stimuli test. Adenosine (100, 200 and 500 mg/kg, ip) produced significant reversal of responses to thermal and chemical stimuli in diabetic rats. 8-Cyclopentyl-1, 3-dipropylxanthine (DPCPX 1 mg/kg, ip), an adenosine A1-receptor antagonist, but not 3,7-dimethyl-1-propargylxanthine (DMPX 1 mg/kg, ip), an adenosine A2A-receptor antagonist, reversed the protective effect of adenosine. These results indicate that adenosine is an effective analgesics in a model of diabetic neuropathy, and the protection produced by adenosine is via stimulation of adenosine A1-receptors.
 ...
PMID:Protective effect of adenosine in diabetic neuropathic pain is mediated through adenosine A1-receptors. 1955 53


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>