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

Bullrout envenomation is known to cause intense pain. Crude bullrout venom and venom fractions were assessed for protease, hyaluronidase, phospholipase and hemolytic activities, reactivity with stonefish antivenom, lethality to brine shrimp and ability to elicit pain in human subjects. Compared with venom obtained from frozen specimens, live fish venom-milking techniques rendered greater venom potency and improved storage characteristics. Although mild proteolytic and hemolytic activity was observed, crude venom demonstrated no hyaluronidase or phospholipase A2 activity, did not affect brine shrimp, or show antigenicity with stonefish antivenom. A single venom protein isolated from bullrout venom is attributed with causing pain in human subjects. The sensations elicited by this novel algesic protein are consistent with chemical stimulation of polymodal nociceptors.
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PMID:An investigation of the biological activity of bullrout (Notesthes robusta) venom. 1066 13

Inflammation causes the induction of cyclooxygenase-2 (Cox-2), leading to the release of prostanoids, which sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity. Peripheral inflammation also generates pain hypersensitivity in neighbouring uninjured tissue (secondary hyperalgesia), because of increased neuronal excitability in the spinal cord (central sensitization), and a syndrome comprising diffuse muscle and joint pain, fever, lethargy and anorexia. Here we show that Cox-2 may be involved in these central nervous system (CNS) responses, by finding a widespread induction of Cox-2 expression in spinal cord neurons and in other regions of the CNS, elevating prostaglandin E2 (PGE2) levels in the cerebrospinal fluid. The major inducer of central Cox-2 upregulation is interleukin-1beta in the CNS, and as basal phospholipase A2 activity in the CNS does not change with peripheral inflammation, Cox-2 levels must regulate central prostanoid production. Intraspinal administration of an interleukin-converting enzyme or Cox-2 inhibitor decreases inflammation-induced central PGE2 levels and mechanical hyperalgesia. Thus, preventing central prostanoid production by inhibiting the interleukin-1beta-mediated induction of Cox-2 in neurons or by inhibiting central Cox-2 activity reduces centrally generated inflammatory pain hypersensitivity.
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PMID:Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. 1126 Jun 97

Intrathecal phospholipase A2 (PLA2) and cyclooxygenase-2 (COX-2), but not COX-1, inhibitors attenuate facilitated pain states generated by peripheral injury/inflammation and by direct activation of spinal glutamate and substance P receptors. These results are consistent with the constitutive expression of PLA2 and COX-2 in spinal cord, the spinal release of prostaglandins by persistent afferent input, and the effects of prostaglandins on spinal excitability. Whereas the acute actions of COX-2 inhibitors are clearly mediated by constitutively expressed spinal COX-2, studies of spinal COX-2 expression indicate that it is upregulated by neural input and circulating cytokines. Given the intrathecal potency of COX-2 inhibitors, the comparable efficacy of intrathecal versus systemic COX-2 inhibitors in hyperalgesic states not associated with inflammation, and the onset of antihyperalgesic activity prior to COX-2 upregulation, it is argued that a principal antihyperalgesic mechanism of COX-2 inhibitors lies with modulation of constitutive COX-2 present at the spinal level.
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PMID:The spinal phospholipase-cyclooxygenase-prostanoid cascade in nociceptive processing. 1180 83

Prostaglandins are important modulators of pain and inflammation. Both, pain and inflammation can be inhibited either at the level of the phospholipase A2 by corticosteroids or at the level of the cyclooxygenase (COX) by non steroidal anti-inflammatory drugs (NSAIDs). Formally, "cyclooxygenase" in general was thought to be responsible for the synthesis of prostaglandins involved in pain, inflammation and fever as well as cytoprotection in the stomach, hemostasis and blood flow in the kidneys. Later, two isoenzymes, cyclooxygenase-1 and cyclooxygenase-2 were discovered. It was postulated cyclooxygenase-1 to exist constitutively and to be responsible for cytoprotection and hemostasis whereas cyclooxygenase-2 is inducible and involved in pain, inflammation and fever. In the meanwhile also constitutive cyclooxygenase-2 was discovered in various tissues. Cyclooxygenase-inhibitors may be divided into four groups: non selective ones (ibuprofen, diclofenac etc.), cyclooxygenase-1 selective inhibitors (SC-560), cyclooxygenase-2 preferential ones (meloxicam) and cyclooxygenase-2 selective inhibitors (celecoxib, rofecoxib, parecoxib). Selective cyclooxygenase-2-inhibitors in opposite to classic non steroidal anti-inflammatory drugs are without effect on bleeding time in therapeutic doses. The most important side effects of non steroidal anti-inflammatory drugs are bleeding, ulceration and perforation in the upper gastrointestinal tract and damage in the kidneys. Selective cyclooxygenase-2-inhibitors show less gastroduodenal ulcerations. Risk patients, however, still need gastroprotection during therapy with cyclooxygenase-2-inhibitors. In patients with low dose aspirin prophylaxis cyclooxygenase-2-inhibitors do not show any benefit compared to classic non steroidal anti-inflammatory drugs (CLASS-study). Less gastrointestinal side effects do not mean a higher overall safety benefit. Cardiovascular and thrombotic side effects of rofecoxib are higher than those of naproxen (VIGOR-study). Concerning valdecoxib, hypersensibilities are reported, probably due to its sulfonamidstructure. The same side effects are to be expected with its prodrug, parecoxib. Drug-drug interactions with cyclooxygenase-2-inhibitors and anticoagulant drugs are to be expected as well as other interactions with drugs, metabolised by the cytochrom P450 system.
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PMID:[Pharmacology of cyclooxygenase 2 inhibition]. 1270 61

Fractionation of an anti-inflammatory extract from Cayaponia tayuya roots yielded two active compounds, identified as 23,24-dihydrocucurbitacin B (1) and cucurbitacin R (2). Both were evaluated for their anti-inflammatory activity on several experimental models of pain and inflammation. In addition, their cytotoxicity and effects on leukotriene B4 (LTB4) formation were evaluated in rat polymorphonuclear leukocytes. Both compounds showed activity in the following models: carrageenan-induced mouse paw oedema (1, 4 mg/kg p.o., 46% inhibition at 3 h), phospholipase A2-induced mouse paw oedema (2, 3 mg/kg i.p., 61% inhibition at 60 min), serotonin-induced mouse paw oedema (1 and 2, 0.5 mg/kg s.c., 73% and 79% inhibition, respectively), 12- O-tetradecanoylphorbol 13-acetate (TPA)-induced acute ear oedema (2, 36% inhibition at 4 mg/kg p.o., and 87% inhibition at 0.1 mg/ear topically). The compounds were also active against the inflammation induced by repeated application of TPA on mouse ears, affecting both the oedema itself (1 and 2 at 0.1 mg/ear, 44% and 56% inhibition, respectively) as well as cell infiltration (68% and 69%, respectively). The activity of both compounds against oedema induced by serotonin was not modified by the glucocorticoid receptor antagonist mifepristone; however, the protein synthesis inhibitor cycloheximide abolished the anti-inflammatory response in both cases. Neither compound modified the production of LTB4 in rat polymorphonuclear leukocytes, nor did they exhibit analgesic properties at the dose assayed.
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PMID:Anti-inflammatory activity of two cucurbitacins isolated from Cayaponia tayuya roots. 1512 85

Vanilloid receptor 1 was recently reported to play an important role in hyperalgesia, but the mechanisms by which this receptor is activated by endogenous inflammatory mediators, such as bradykinin and nerve growth factor, are not yet fully understood. Here, we investigated whether bradykinin, which is a pain-producing inflammatory mediator, sensitizes vanilloid receptor 1 by inducing the activation of cyclooxygenases, phospholipase C and phospholipase A2 in rat dorsal root ganglion cells. We demonstrated this using 45Ca2+ uptake and inositol phosphates accumulation assays, bradykinin activates phospholipase C and cyclooxygenase-1 through the bradykinin B2 receptor. The bradykinin B2 receptor then sensitizes vanilloid receptor 1 activity by facilitating non-selective Ca2+ channel activity, increasing the intracellular Ca2+ concentration from the extracellular pool. These methods would be useful for screening new drugs for activity at vanilloid receptor 1. These data suggest that endogenous substances produced by several enzymes may be capable of producing a synergistic response involving the vanilloid receptor 1.
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PMID:Sensitization of vanilloid receptor 1 induced by bradykinin via the activation of second messenger signaling cascades in rat primary afferent neurons. 1536 73

The present study was carried out, using inhibitors to secretory phospholipase A2 (sPLA2, 12-epi-scalaradial), cytosolic phospholipase A2 (cPLA2, AACOCF3), or calcium-independent phospholipase A2 (iPLA2, bromoenol lactone), to compare possible contributions of central nervous PLA2 isoforms to the development of allodynia after facial carrageenan injection in mice. C57BL/6J (B6) mice showed increased responses to facial stimulation using a von Frey hair (1 g force), at 8 h, 1 day, and 3 days after facial carrageenan injection. On the other hand, BALB/c mice did not show increased responses at any of the time points. In both B6 and BALB/c mice, intracerebroventricular injection of inhibitors to each of the three PLA2 isoforms significantly reduced responses to von Frey hair stimulation at 8 h and 1 day after facial carrageenan injection, but at 3 days after injection, only the sPLA2 inhibitor had an effect. Since BALB/c mice did not show increased responses after facial carrageenan injection, the reduction in responses actually indicates that there is loss of normal sensitivity to von Frey hair stimulation after intracerebroventricular injection of each of these inhibitors, in this strain of mice. The effects of PLA2 inhibitors are unlikely to be due simply to inhibition of arachidonic acid generation, since intracerebroventricular injection of arachidonic acid also had an anti-nociceptive effect. The above results support an important role of central nervous PLA2s in neurotransmission and pain transmission.
Pain 2004 Nov
PMID:Intracerebroventricular injection of phospholipases A2 inhibitors modulates allodynia after facial carrageenan injection in mice. 1549 95

The accidents caused by Thalassophryne maculosa fish venoms are frequent and represent a public health problem in some regions of Venezuela. Most accidents occur in the fishing communities and tourists. The clinical picture is characterized by severe pain, dizziness, fever, edema, and necrosis. Due to the lack of efficient therapy it may take weeks, or even months for complete recovery of the victims. The investigations presented here were undertaken to assess the eletrophoretical profile and principal biological properties of the T. maculosa venom. Venom obtained from fresh captured specimens of this fish was tested in vitro or in animal models for a better characterization of its toxic activities. In contrast to other fish venoms, T. maculosa venom showed relative low LD50. The injection of venom in the footpad of mice reproduced a local inflammatory lesion similar to that described in humans. Significant increase of the nociceptive and edematogenic responses was observed followed within 48 h by necrosis. Pronounced alterations on microvascular hemodynamics were visualized after venom application. These alterations were represented by fibrin depots and thrombus formation followed by complete venular stasis and transient arteriolar contraction. T. maculosa venom is devoid of phospholipase A2 activity, but the venom showed proteolytic and myotoxic activities. SDS-Page analysis of the crude venom showed important bands: one band located above 97 M(w), one band between 68 and 97 M(w), one major band between 29 and 43 M(w) and the last one located below 18.4 M(w) Then, the results presented here support that T. maculosa venom present a mixture of bioactive toxins involved in a local inflammatory lesion.
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PMID:Important biological activities induced by Thalassophryne maculosa fish venom. 1562 64

Stings of fire corals, potent hydroids common in the Red Sea, are known to cause severe pain and they develop burns and itching that lasts few hours after contact. Nematocyst venom of Millepora platyphylla (Mp-TX) was isolated according to a recent method developed in our laboratory to conduct a previous investigation on the nematocyst toxicity of Millepora dichotoma and M. platyphylla. In this study, Mp-TX was fractionated by using both gel filtration and ion exchange chromatography. Simultaneous biological and biochemical assays were performed to monitor the hemolytic (using washed human red blood cells, RBCs) and phospholipase A2 (using radiolabeled sn-2 C14-arachidonyl phosphatidylcholine as a substrate) active venom fractions. The magnitude of both hemolysis and phospholipase A2 activity was found in a fraction rich of proteins of molecular masses approximately 30,000-34,000 Daltons. The former fraction was purified by ion exchange chromatography, and a major bioactive protein factor (approx. 32,500 Daltons , here named milleporin-1) was recovered. Milleporin-1 enzymatic activity showed a significant contribution to the overall hemolysis of human RBCs. This activity, however, could not be completely inhibited using phospholipid substrates. Melliporin-1 fraction retained about 30% hemolysis, until totally rendered inactive when boiled for 3 min. The overall mechanism of action of milleporin-1 to impact the cellular membrane was discussed; however, it is pending more biochemical and pharmacological future studies.
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PMID:Milleporin-1, a new phospholipase A2 active protein from the fire coral Millepora platyphylla nematocysts. 1568 37

Recent research in our laboratory has demonstrated that stress activates an endogenous cannabinoid mechanism that suppresses sensitivity to pain [Nature 435 (2005) 1108]. In this work, CB(1) antagonists administered systemically blocked stress-induced analgesia induced by brief, continuous foot-shock. The present studies were conducted to examine the role of cannabinoid CB(1) receptors in the brainstem rostral ventromedial medulla (RVM) and midbrain dorsolateral periaqueductal gray (PAG) in cannabinoid stress-induced analgesia (SIA). Pharmacological blockade of vanilloid TRPV1 receptors with capsazepine, administered systemically, did not alter cannabinoid SIA, suggesting that cannabinoid SIA was not dependent upon TRPV1. Microinjection of the competitive CB(1) antagonist rimonabant (SR141716A) into either the RVM or dorsolateral PAG suppressed stress antinociception in this model. Rimonabant was maximally effective following microinjection into the dorsolateral PAG. The fatty-acid amide hydrolase (FAAH) inhibitor arachidonoyl serotonin (AA-5-HT) was subsequently used to block hydrolysis of endocannabinoids and enhance SIA. Systemic and site-specific injections of AA-5-HT into either the dorsolateral PAG or RVM induced CB(1)-mediated enhancements of SIA. Palmitoyltrifluoromethylketone, a potent inhibitor of FAAH and phospholipase A2 activity, administered systemically, exerted similar effects. In all conditions, the antinociceptive effects of each FAAH inhibitor were completely blocked by coadministration of the CB(1) antagonist rimonabant. The present results provide evidence that a descending cannabinergic neural system is activated by environmental stressors to modulate pain sensitivity in a CB(1)-dependent manner.
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PMID:Inhibition of fatty-acid amide hydrolase enhances cannabinoid stress-induced analgesia: sites of action in the dorsolateral periaqueductal gray and rostral ventromedial medulla. 1612 56


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