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

Despite abundant evidence implicating the importance of N-methyl-D-aspartate (NMDA) receptors in the spinal cord for pain transmission, the signal transduction coupled to NMDA receptor activation is largely unknown for the neuropathic pain state that lasts over periods of weeks. To address this, we prepared mice with neuropathic pain by transection of spinal nerve L5. Wild-type, NR2A-deficient, and NR2D-deficient mice developed neuropathic pain; in addition, phosphorylation of NR2B subunits of NMDA receptors at Tyr1472 was observed in the superficial dorsal horn of the spinal cord 1 week after nerve injury. Neuropathic pain and NR2B phosphorylation at Tyr1472 were attenuated by the NR2B-selective antagonist CP-101,606 and disappeared in mice lacking Fyn kinase, a Src-family tyrosine kinase. Concomitant with the NR2B phosphorylation, an increase in neuronal nitric oxide synthase activity was visualized in the superficial dorsal horn of neuropathic pain mice by NADPH diaphorase histochemistry. Electron microscopy showed that the phosphorylated NR2B was localized at the postsynaptic density in the spinal cord of mice with neuropathic pain. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, and PGE receptor subtype EP1-selective antagonist reduced the NR2B phosphorylation in these mice. Conversely, EP1-selective agonist stimulated Fyn kinase-dependent nitric oxide formation in the spinal cord. The present study demonstrates that Tyr1472 phosphorylation of NR2B subunits by Fyn kinase may have dual roles in the retention of NMDA receptors in the postsynaptic density and in activation of nitric oxide synthase, and suggests that PGE2 is involved in the maintenance of neuropathic pain via the EP1 subtype.
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PMID:Fyn kinase-mediated phosphorylation of NMDA receptor NR2B subunit at Tyr1472 is essential for maintenance of neuropathic pain. 1619 Aug 98

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequently prescribed drug for the treatment of inflammation and pain. However, conventional NSAIDs and selective COX-2 inhibitors have shown many side effects such as gastric mucosal damage and cardiovascular problems. Recently, the use of dual acting inhibitors of cyclooxygenases (COX) and lipoxygenase (LOX) has been highlighted for their minimized side effects compared to NSAIDs. The objective of the present study was to examine the efficacy and the gastric side effects of 1-furan-2-yl-3-pyridin-2-yl-propenone (FPP-3), a synthetic dual inhibitor of COX/5-LOX. Indomethacin (1-50 mg/kg, p.o.), a non-selective COX inhibitor, and FPP-3 (0.5-50 mg/kg, p.o.), a dual inhibitor, significantly suppressed the carrageen-induced paw edema with different pharmacological profiles. The concentrations of FPP-3 and indomethacin showing 50% inhibition of the maximum paw edema in rats were 10 mg/kg and 20 mg/kg, respectively. More importantly, there were no gastric ulcers formed in FPP-3-treated rats and mice, whereas indomethacin caused gastric mucosal bleeding in a concentration-dependent manner. In addition, FPP-3 showed an analgesic effect in acetic acid-induced writhing response in mice in a dose-dependent manner. The results suggest that FPP-3 may have a benefit in combatting inflammation and pain by dual inhibition of COX and LOX.
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PMID:Potent analgesic and anti-inflammatory activities of 1-furan-2-yl-3-pyridin-2-yl-propenone with gastric ulcer sparing effect. 1646 46

Neuraxial administration of nonsteroid antiinflammatory drugs has been suggested as an alternative in the management of intractable pain, but there is little evidence that the neurotoxic effects of indomethacin by this route of administration have been evaluated. In this study, we evaluated histological neurotoxicity of indomethacin after its subarachnoid administration in guinea pigs. The hypothesis tested was "Does subarachnoid administration of indomethacin produce damage in the spinal cord of guinea pigs?" Ten male guinea pigs were anesthetized, and a polyamide catheter connected to a subcutaneous osmotic micro-pump was implanted at the L2-3 level. Animals were randomly assigned in 2 groups of 5 animals each. Indomethacin or saline solution was administered by continuous infusion (0.5 microL/h) for 14 days. Neurotoxicity was determined by spinal cord histopathology. There was no evidence of toxicity in the histological examinations of either group. These data suggest that subarachnoid administration of indomethacin infusion, at these doses, did not produce lesions typical of neurotoxicity in the spinal cord. We have concluded that epidural administration of indomethacin may be considered an alternative for application in human pain management, although more studies to determine its safety are required.
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PMID:Chronic subarachnoid administration of 1-(4chlorobenzoyl)-5methoxy-2methyl-1H-indole-3 acetic acid (indomethacin): an evaluation of its neurotoxic effects in an animal model. 1679 Jun 34

The first patient with chronic paroxysmal hemicrania has been followed for 45 years, and for 33 years with indomethacin treatment. The headache became less severe with time; there was no indomethacin tachyphylaxis. The first patient with SUNCT was followed for 28 years, until his demise at 89. Pain became worse with time. No adequate therapy was found. The first patient with Hemicrania continua was followed for 19 years, until her demise at 81. She was treated with indomethacin during the whole observation time. There was no tachyphylaxis. Both patients treated with indomethacin developed gastric ulcer. And both had gastric surgery. Indomethacin therapy may be a life-long affair. The risk of gastric complications may be substantial.
J Headache Pain 2006 Jun
PMID:Chronic paroxysmal hemicrania, hemicrania continua and SUNCT: the fate of the three first described cases. 1681 54

The first patient with chronic paroxysmal hemicrania (CPH), a 41-year-old woman, first seen in 1961, was followed until an adequate treatment was found, 12 years later. Clinically, attack frequency and duration differed widely from the general pattern of cluster headache. Ocular variables, such as intraocular pressure and corneal indentation pulse amplitudes, also differed in our case (clear symptomatic side increment during attacks) and cluster headache. Pupil reactions to directly and indirectly acting sympathicomimetic drugs were also vastly different in our case and cluster headache: no signs of Horner s syndrome in our patient, while cluster headache exhibits a "Horner-like pattern." In cluster headache, there is a relative hypohidrosis in the forehead on the symptomatic side if body temperature is increased, and a clear hyperhidrosis on direct parasympathomimetic stimulation. This was not so in our case. Indomethacin was highly effective in our case, while "cluster headache drugs," such as ergotamine/sumatriptan, were ineffective. Indomethacin was inactive in cluster headache. Accordingly, our case seemed to differ decisively from cluster headache: CPH had been discovered.
Curr Pain Headache Rep 2006 Aug
PMID:Chronic paroxysmal hemicrania: from the index patient to the disease. 1683 45

Indomethacin is a nonsteroidal anti-inflammatory drug used frequently to control chronic or temporary pain. In the kidney, indomethacin decreases medullary and cortical perfusion, resulting in hypoxia. Kidney hypoxia has many effects, including changes in gene expression, and is a strong stimulus for angiogenesis. Other angiogenic factors include vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2), transforming growth factor beta 1 (TGFbeta1), and platelet-derived growth factor (PDGF). Our goal was to examine the influence of indomethacin on mRNA expression of these factors and their selected receptors in the renal cortex of healthy rats. Groups of 8 healthy, male, six-week-old Wistar rats received either indomethacin (5 mg/kg/day) or placebo orally for three months. RNA from renal cortex biopsies was analyzed by real-time polymerase chain reaction to quantify the mRNA levels of each cytokine. We observed significantly higher mRNA levels for VEGF (1.73-fold), FGF-2 (5.6-fold) and TGFbeta receptor III (2.93-fold), PDGF receptor alpha (2.93-fold) and receptor beta (2.91-fold) in rats receiving indomethacin compared to rats given placebo (p < 0.05). Amounts of mRNA for TGFbeta1, PDGF, FGF receptors 1 and 2 and TGFbeta receptor I did not differ between analysed groups. Our data indicates that indomethacin may regulate the expression of potent angiogenic factors VEGF and FGF-2.
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PMID:The effects of indomethacin on angiogenic factors mRNA expression in renal cortex of healthy rats. 1744 Feb 34

Recent research showed the involvement of prostaglandin E receptor subtype 4 (EP4) in hypersensitivity to inflammatory pain and suggested that the EP4 receptor is a potential target for the pharmacological treatment of inflammatory pain. We examined the effects of (S)-4-(1-(5-chloro-2-(4-fluorophenyoxy) benzamido)ethyl) benzoic acid (CJ-42794), a selective EP4 antagonist, on gastrointestinal ulcerogenic and healing responses in rats, in comparison with those of various cyclooxygenase (COX) inhibitors. CJ-42794 alone, given p.o., did not produce any damage in the gastrointestinal mucosa, similar to 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560) (COX-1 inhibitor) or rofecoxib (COX-2 inhibitor), whereas indomethacin (nonselective COX inhibitor) caused gross lesions. Rofecoxib but not CJ-42794, however, damaged these tissues when coadministered with SC-560 and aggravated gastric lesions produced by aspirin. Indomethacin and SC-560 worsened the gastric ulcerogenic response to cold-restraint stress, yet neither CJ-42794 nor rofecoxib had any effect. Furthermore, indomethacin and SC-560 at lower doses damaged the stomach and small intestine of adjuvant arthritic rats. In arthritic rats, rofecoxib but not CJ-42794 provoked gastric ulceration, whereas CJ-42794 produced little damage in the small intestine. The repeated administration of CJ-42794 and rofecoxib as well as indomethacin impaired the healing of chronic gastric ulcers with a down-regulation of vascular endothelial growth factor expression in the ulcerated mucosa. These results suggest that CJ-42794 does not cause any damage in the normal rat gastrointestinal mucosa and in the arthritic rat stomach and does not worsen the gastric ulcerogenic response to stress or aspirin in normal rats, although this agent slightly damages the small intestine of arthritic rats and impairs the healing of gastric ulcers.
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PMID:Effect of (S)-4-(1-(5-chloro-2-(4-fluorophenyoxy)benzamido)ethyl) benzoic acid (CJ-42794), a selective antagonist of prostaglandin E receptor subtype 4, on ulcerogenic and healing responses in rat gastrointestinal mucosa. 1757

Non-steroidal anti-inflammatory drugs (NSAIDs) are common in alleviating pain, pyrexia and inflammation, in patients with rheumatoid arthritis and osteoarthritis. As these drugs are associated with high incidence of gastrointestinal ulceration, bleeding and kidney damage which may be linked with lipid peroxidation. our study was aimed to examine lipid peroxidation induction capacity of NSAIDs (diclofenac sodium, ibuprofen, flurbiprofen, paracetamol, nimesulide, celecoxib and indomethacin) by determining 4-hydroxy-2-nonenal (4-HNE) concentration as an index of lipid peroxidation and to see the suppressive potential of ascorbic acid on NSAID induced lipid peroxidation. The results suggest that diclofenac sodium, ibuprofen, flurbiprofen, paracetamol, nimesulide and celecoxib exerted mild antioxidant activity. Indomethacin exerted statistically significant increase in 4-HNE content, indicating statistically significant peroxidation activity. Ascorbic acid could significantly reduce indomethacin-induced lipid peroxidation.
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PMID:Exploring effects of different nonsteroidal antiinflammatory drugs on lipid peroxidation. Part II. 4-HNE profile. 1769 42

We examined a possible involvement of cyclooxygenase (COX) and nitric oxide synthase (NOS) products in hyperalgesia occurring during streptozotocin (STZ)-induced diabetes. Indomethacin and celecoxib were used as relatively selective inhibitors of COX-1 and COX-2, respectively. NOS inhibitors included: non-specific inhibitor N(G)-nitro-L-arginine and L-N(6)-(1-iminoethyl)lysine preferentially acting on inducible NOS (iNOS) as well as 7-nitroindazole relatively specific inhibitor neuronal NOS (nNOS). The above-mentioned agents, except 7-nitroindazole, suppressed hyperalgesia occurring after administration of STZ. The results of the study suggest participation of COX-1, COX-2 and iNOS, but not nNOS, in transmission of pain stimuli in STZ-induced diabetic hyperalgesia.
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PMID:Effect of cyclooxygenase and nitric oxide synthase inhibitors on streptozotocin-induced hyperalgesia in rats. 1798 4

Membrane fusion is an important event in many biological processes and is characterized by several intermediate steps of which content mixing between the two fusing vesicles signals the completion of the process. Fusion induced solely by small drug molecules is not a common event. Non Steroidal Anti-Inflammatory Drugs (NSAIDs), that control pain and inflammation, are also capable of exhibiting diverse functions. In this study we present a new function of NSAIDs belonging to the oxicam group, as membrane fusogenic agents. Small Unilamellar Vesicles (SUVs) formed by the phospholipid, dimyristoylphosphatidylcholine (DMPC), were used as model membranes. Fluorescence assays using terbium/dipicolinic acid (Tb/DPA) were used to monitor content mixing and corresponding leakage in presence of the drugs. Transmission Electron Microscope (TEM) was also used to image fusion bodies in drug treated vesicles as compared to the untreated ones. The results show that the three oxicam NSAIDs viz. Meloxicam, Piroxicam and Tenoxicam can induce fusion of DMPC vesicles and lead the fusion process to completion at a very low drug to lipid ratio (D/L) of 0.045. The oxicam drugs exhibit differential fusogenic behavior as reflected in the kinetics of content mixing and leakage, both of which can be described by a single exponential rate equation. Moreover, not all NSAIDs can induce membrane fusion. Indomethacin, an acetic acid group NSAID and ibuprofen, a propionic acid group NSAID, did not induce fusion of vesicles. This new property of NSAIDs has important applications in biochemical processes.
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PMID:Membrane fusion: a new function of non steroidal anti-inflammatory drugs. 1861 19


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