Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A pharmacological concept of topical peripheral pain therapy with a combination of a sodium channel blocker from the class of local anesthetics and a non-steroidal anti-inflammatory drug (NSAID) from the class of nonselective/ partially selective cyclooxygenase (COX) inhibitors is described. The dual mechanism of action of these substances on the cellular level interferes with pain components of both inflammatory and neuronal genesis and is functionally synergistic. This enables the combination of these agents to produce a more long-lasting analgesia than is attainable with either of the substances alone. The therapeutic indication is the symptomatic reduction of neuromuscular pain of traumatic or metabolic origin. The already more favorable safety profile for topical applications can be improved further by a possible dose reduction of the two substances.
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PMID:Pharmacological concept for topical synergistic analgesia of peripheral neuromuscular pain. 1657 26

Postoperative pain requires treatment not only to provide comfort to patients but also to improve postoperative outcome. Anti-inflammatory compounds are an important component of multimodal analgesia in the postoperative period. The newer cyclooxygenase (COX)-2 inhibitors are as effective as classical nonsteroidal anti-inflammatory drugs (NSAIDs) in this setting. However, COX-2 inhibitors offer a number of advantages over NSAIDs when used to treat postoperative pain. These include a reduced incidence of gastrointestinal ulceration and no inhibitory effect on platelet function and thereby a reduced risk of blood loss. Other benefits are less impairment of bone healing and no induction of bronchospasm in patients with aspirin-sensitive asthma. Increased cardiovascular thromboembolic events by COX-2 inhibitors have been reported after coronary artery bypass graft surgery only, but in general, surgery studies the incidence of such complications was comparable to placebo. Overall, COX-2 inhibitors offer a number of advantages over classical NSAIDs in the postoperative pain setting, but require the same caution with regard to renal effects.
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PMID:The role of COX-2 inhibitors in the treatment of postoperative pain. 1678 36

Studies of hypersensitivity to mechanical stimuli after incisional surgery suggest that cyclooxygenase (COX)-1, but not COX-2, in the spinal cord participates in postoperative pain. In the current study, we sought to determine the role of COX isoenzymes after laparotomy, examining spontaneous exploratory behavior rather than withdrawal reflexes. Adult male Sprague-Dawley rats underwent subcostal laparotomy surgery under isoflurane anesthesia or received anesthesia without surgery. Exploratory locomotor activity was measured on the first postoperative day after intrathecal injection of dimethyl sulfoxide (vehicle) or COX-1 (SC-560) or COX-2 (NS-398) inhibitors. Laparotomy reduced ambulation, rearing, and rapid small movements (stereotypy) similarly in animals without intrathecal catheters and those receiving intrathecal vehicle control. SC-560 produced a dose-related return to normal exploratory behavior with complete return at doses of 20 mug and larger. In contrast, NS-398 in doses up to 50 mug failed to increase exploratory behavior. These data with exploratory behavior and laparotomy agree with studies with reflexive withdrawal responses after incisional surgery and indicate that COX-1 inhibition reduces pain responses after surgery. Spinal COX-1 inhibition completely restores exploratory activity, including rearing behavior that stretches the abdominal muscles. These data suggest that targeting COX-1 in the spinal cord may produce postoperative analgesia.
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PMID:Intrathecal administration of a cylcooxygenase-1, but not a cyclooxygenase-2 inhibitor, reverses the effects of laparotomy on exploratory activity in rats. 1693 82

Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently the most widely used class of therapeutic agents. By inhibiting cyclooxygenase (COX) and reducing gastrointestinal prostaglandins, they provide effective analgesia and suppress inflammation in a variety of conditions. However, through the same mechanism of COX inhibition, they also cause significant gastrointestinal toxicity. One of the most common methods to reduce NSAID-induced gastrointestinal toxicity has been to co-prescribe prophylactic therapies such as acid-reducing agents or the synthetic prostaglandin analogue, misoprostol. More recently safer NSAIDs, such as the COX-2 specific NSAIDs or the nitric oxide-releasing NSAIDs, have been developed or are currently in development. This article reviews mechanisms of NSAID-induced gastrointestinal toxicity. Also reviewed are data on the gastrointestinal consequences of the prophylatic co-therapies, COX-2 specific NSAIDs and nitric oxide-releasing NSAIDs.
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PMID:Nonsteroidal anti-inflammatory drug gastrointestinal toxicity. 1702 93

DP-155 is a lipid prodrug of indomethacin that comprises the latter conjugated to lecithin at position sn-2 via a 5-carbon length linker. It is cleaved by phospholipase A2 (PLA)(2) to a greater extent than similar compounds with linkers of 2, 3, and 4 carbons. Indomethacin is the principal metabolite of DP-155 in rat serum and, after DP-155 oral administration, the half-life of the metabolite was 22 and 93 h in serum and brain, respectively, compared to 10 and 24 h following indomethacin administration. The brain to serum ratio was 3.5 times higher for DP-155 than for indomethacin. In vitro studies demonstrated that DP-155 is a selective cyclooxygenase (COX)-2 inhibitor. After it is cleaved, its indomethacin derivative nonselectively inhibits both COX-1 and -2. DP-155 showed a better toxicity profile probably due to the sustained, low serum levels and reduced maximal concentration of its indomethacin metabolite. DP-155 did not produce gastric toxicity at the highest acute dose tested (0.28 mmol/kg), while indomethacin caused gastric ulcers at a dose 33-fold lower. Furthermore, after repeated oral dosing, gastrointestinal and renal toxicity was lower (10- and 5-fold, respectively) and delayed with DP-155 compared to indomethacin. In addition to reduced toxicity, DP-155 had similar ameliorative effects to indomethacin in antipyretic and analgesia models. Moreover, DP-155 and indomethacin were equally efficacious in reducing levels of amyloid ss (Ass)42 in transgenic Alzheimer's disease mouse (Tg2576) brains as well as reducing Ass42 intracellular uptake, neurodegeneration, and inflammation in an in vitro AD model. The relatively high brain levels of indomethacin after DP-155 administration explain the equal efficacy of DP-155 despite its low systemic blood concentrations. Compared to indomethacin, the favored safety profile and equal efficacy of DP-155 establish the compound as a potential candidate for chronic use to treat AD-related pathology and for analgesia.
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PMID:DP-155, a lecithin derivative of indomethacin, is a novel nonsteroidal antiinflammatory drug for analgesia and Alzheimer's disease therapy. 1762 76

The amplification of pain long after the initial stimulus may be avoided if the treatment of pain is introduced before its initiation. However, conflicting evidence exists about the efficacy of such preemptive analgesia for the management of postoperative pain. This study compares the efficacy of intraplantar administration of indomethacin (a non-selective inhibitor of cyclooxygenase) and MK886 (an inhibitor of 5-lipoxygenase-activating protein), separately or in combination to produce preemptive analgesia in a model of surgical incisional pain in male Wistar rats. All incised rats (5 to 6 rats per group) had allodynia at 2, 6, and 24 h after surgery as evaluated using von Frey filaments. MK886, but not indomethacin (50 to 200 microg/paw), reduced the allodynia when injected either 1 h before or 1 h after surgery. The effect of preoperative MK886 (160 microg/paw) against incisional allodynia had a magnitude apparently similar to that produced by postoperative MK886. Pre-, but not postoperative MK886 (80 microg/paw) reduced the allodynia but the effect was seen only at 6 h after surgery. In contrast, MK886 (40 microg/paw) intensified the allodynia observed 2 h after the incision either injected before or after surgery. MK886 or indomethacin alone did not provide preemptive analgesia in the model of incisional pain. In contrast, the combination of MK886 with indomethacin reduced the allodynia more effectively when used before than after surgery, thus fulfilling the criteria for preemptive analgesia. In conclusion, preoperative inhibition of the local generation of both prostaglandins and leukotrienes by surgical incision may be an alternative to provide preemptive analgesia.
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PMID:Comparison of pre- versus post-incision administration of intraplantar indomethacin and MK886 in a rat model of postoperative pain. 1766 52

Cannabinoid CB1 and CB2 receptors are located at key sites involved in the relaying and processing of noxious inputs. Both CB1 and CB2 receptor agonists have analgesic effects in a range of models of inflammatory and neuropathic pain. Importantly, clinical trials of cannabis-based medicines indicate that the pre-clinical effects of cannabinoid agonists may translate into therapeutic potential in humans. One of the areas of concern with this pharmacological approach is that CB1 receptors have a widespread distribution in the brain and that global activation of CB1 receptors is associated with adverse side effects. Studies of the endogenous cannabinoids (endocannabinoids) have demonstrated that they are present in most tissues and that in some pain states, such as neuropathic pain, levels of endocannabinoids are elevated at key sites involved in pain processing. An alternative approach that can be used to harness the potential therapeutic effects of cannabinoids is to maximise the effects of the endocannabinoids, the actions of which are terminated by re-uptake and metabolism by various enzymes, including fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL) and cyclooxygenase type 2 (COX2). Preventing the metabolism, or uptake, of endocannabinoids elevates levels of these lipid compounds in tissue and produces behavioural analgesia in models of acute pain. Herein we review recent studies of the effects of inhibition of metabolism of endocannabinoids versus uptake of endocannabinoids on nociceptive processing in models of inflammatory and neuropathic pain.
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PMID:Endocannabinoid metabolism and uptake: novel targets for neuropathic and inflammatory pain. 1789 Nov 56

One of the most distressing symptoms of many neuropathic pain syndromes is the enhanced pain sensation to tactile or thermal stimulation (hyperalgesia). In the present study we used functional magnetic resonance imaging (fMRI) and explored brain activation patterns during acute impact pain and mechanical hyperalgesia in the human ultraviolet (UV)-B model. To investigate pharmacological modulation, we examined potential differential fMRI correlates of analgesic and antihyperalgesic effects of two intravenous cyclooxygenase inhibitors, i.e. parecoxib and acetylsalicylic acid (ASA). Fourteen healthy volunteers participated in this double-blinded, randomized and placebo-controlled crossover study. Tactile stimuli and mechanical impact hyperalgesia were tested at the site of a UV-B irradiation and acute mechanical pain was tested at a site distant from the irradiated skin. These measurements were conducted before and 30 min after a 5-min intravenous infusion of either saline (placebo), parecoxib 40 mg or ASA 1000 mg. Acute mechanical pain and mechanical hyperalgesia led to widespread activations of brain areas known to comprise the human pain matrix. Analgesic effects were found in primary (S1) and secondary (S2) somatosensory cortices, parietal association cortex (PA), insula, anterior parts of the cingulate cortex and prefrontal cortices. These brain areas were also modulated under antihyperalgesic conditions. However, we observed a greater drug-induced modulation of mainly PA and inferior frontal cortex during mechanical hyperalgesia; during acute mechanical pain there was a greater modulation of mainly bilateral S2. Therefore, the results of the present study suggest that there is a difference in the brain areas modulated by analgesia and antihyperalgesia.
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PMID:Brain imaging of analgesic and antihyperalgesic effects of cyclooxygenase inhibition in an experimental human pain model: a functional MRI study. 1776 11

Acetaminophen is the most used analgesic/antipyretic drug. Its unclear mechanism of action could rely on cyclooxygenase inhibition, NO synthesis blockade or reinforcement of the serotonergic system. Here we show that in thermal, mechanical and chemical pain tests, AM-251, a specific CB(1) receptor antagonist, abolished the analgesic action of acetaminophen, which was also lost in CB(1) receptor knockout mice. Moreover, acetaminophen was shown unable to bind to CB(1) receptors demonstrating an indirect involvement of these receptors in the analgesic effect of this compound. Accordingly with these results, we also demonstrated that the inhibition of FAAH, an enzyme involved in the cerebral metabolism of acetaminophen into AM404, known to reinforce the activity of the endocannabinoid system, suppressed the antinociceptive effect of acetaminophen. In addition, similarly to the interaction of acetaminophen with bulbospinal serotonergic pathways and spinal serotonin receptors, we observed that the antinociceptive activity of ACEA, a CB(1) receptor agonist, was inhibited by lesion of bulbospinal serotonergic pathways and antagonists of spinal 5-HT receptors. We therefore propose that acetaminophen-induced analgesia could involve the following sequence: (1) FAAH-dependent metabolism of acetaminophen into AM404; (2) indirect involvement of CB(1) receptors by this metabolite; (3) endocannabinoid-dependent reinforcement of the serotonergic bulbospinal pathways, and (4) involvement of spinal pain-suppressing serotonergic receptors.
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PMID:Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia. 1848 96

Peroxynitrite (ONOO(-)), the reaction product of the interaction between superoxide (O(2)(*-)) and nitric oxide (*NO), is a potent proinflammatory and cytotoxic nitrooxidative species. Its role as a mediator of hyperalgesia (clinically defined as an augmented sensitivity to painful stimuli) is not known. In light of the known proinflammatory properties of ONOO(-), our study addressed its potential involvement in the development of hyperalgesia associated with tissue damage and inflammation. Intraplantar injection in rats of the ONOO(-) precursor O(2)(*-) (1 microM) led to the development of thermal hyperalgesia associated with a profound localized inflammatory response. Both events were blocked by L-NAME (N(G)-nitro-L-arginine methyl ester, 3-30 mg/kg), a nitric oxide synthase inhibitor, or by FeTM-4-PyP(5+) [Fe(III)5,10,15,20-tetrakis(N-methylpyridinium-4-yl)porphyrin, 3-30 mg/kg], an ONOO(-) decomposition catalyst. These results suggested that locally synthesized ONOO(-) produced in situ by O(2)(*-) and *NO is key in the development of inflammatory hyperalgesia. The direct link between ONOO(-) and hyperalgesia was further supported by demonstrating that intraplantar injection of soluble ONOO(-) itself (1 microM) similarly led to inflammatory hyperalgesia. ONOO(-) generated by the interaction between exogenous administration of O(2)(*-) and endogenous *NO, or provided by direct injection of ONOO(-), activated the transcription factor NF-kappaB in paw tissues, enhancing expression of the inducible but not the constitutive cyclooxygenase enzyme (COX-2 and COX-1, respectively). ONOO(-)-mediated hyperalgesia was blocked in a dose-dependent manner by intraperitoneal injections of indomethacin (10 mg/kg), a nonselective COX-1/COX-2 inhibitor, or NS398 [N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; 10 mg/kg] a selective COX-2 inhibitor, as well as by an anti-prostaglandin (PG) E(2) antibody (200 microg). In another established model of inflammation-related hyperalgesia by intraplantar injection of carrageenan in rats, inhibition of ONOO(-) with FeTM-4-PyP(5+) (3-30 mg/kg) inhibited the development of hyperalgesia and the release of PGE(2) in paw tissue exudates. Furthermore, FeTM-4-PyP(5+) synergized with indomethacin and NS397 (1-10 mg/kg) to block both hyperalgesia and edema. Taken together, these data show for the first time that ONOO(-) is a potent mediator of inflammation-derived hyperalgesia operating via the COX-to-PGE(2) pathway. These results provide a pharmacological rationale for the development of inhibitors of peroxynitrite biosynthesis as novel nonnarcotic analgesics. The broad implications of our study are that dual inhibition of both ONOO(-) formation and COX activity may provide an alternative therapeutic approach to the management of pain: effective analgesia with reduced side-effects typically associated with the use of COX inhibitors.
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PMID:Cyclooxygenases 1 and 2 contribute to peroxynitrite-mediated inflammatory pain hypersensitivity. 1849 4


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