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)

Lactoferrin (LF) is a ubiquitous protein which exists in milk, plasma, synovial fluids, cerebrospinal fluid and other biological fluids. LF is also well known as a natural immunomodulator. Recently, we found that bovine milk-derived LF (BLF) produced micro-opioid receptor-mediated analgesia. In this study, we examined whether oral administration of BLF causes anti-nociceptive and anti-inflammatory effects, and also whether it modulates LPS-induced TNF-alpha and IL-10 production in rat model of rheumatoid arthritis (RA), rat adjuvant arthritis. BLF was administrated once daily, starting 3 hr before (preventive experiment) or 19 days after (therapeutic experiment) adjuvant injection. In both experiments, BLF suppressed the development of arthritis and the hyperalgesia in the adjuvant-injected paw. The single-administered BLF produced a dose-dependent analgesia, which was reversed by naloxone, in the adjuvant arthritis rats. Both repeated and single administration of BLF suppressed TNF-alpha production and increased IL-10 production in the LPS-stimulated adjuvant arthritis rats. These results suggest that orally administered BLF has both preventive and therapeutic effects on the development of adjuvant-induced inflammation and pain. Moreover, the immunomodulatory properties of BLF, such as down-regulation of TNF-alpha and up-regulation of IL-10, could be beneficial in the treatment of RA. Thus, we concluded that LF can be safely used as a natural drug for RA patients suffering from joint pain.
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PMID:Oral administration of lactoferrin inhibits inflammation and nociception in rat adjuvant-induced arthritis. 1503 42

We describe the properties of a novel nonpeptide kinin B1 receptor antagonist, NVP-SAA164, and demonstrate its in vivo activity in models of inflammatory pain in transgenic mice expressing the human B1 receptor. NVP-SAA164 showed high affinity for the human B1 receptor expressed in HEK293 cells (K(i) 8 nM), and inhibited increases in intracellular calcium induced by desArg10kallidin (desArg10KD) (IC50 33 nM). While a similar high affinity was observed in monkey fibroblasts (K(i) 7.7 nM), NVP-SAA164 showed no affinity for the rat B1 receptor expressed in Cos-7 cells. In transgenic mice in which the native B1 receptor was deleted and the gene encoding the human B1 receptor was inserted (hB1 knockin, hB1-KI), hB1 receptor mRNA was induced in tissues following LPS treatment. No mRNA encoding the mouse or human B1 receptor was detected in mouse B1 receptor knockout (mB1-KO) mice following LPS treatment. Freund's complete adjuvant-induced mechanical hyperalgesia was similar in wild-type and hB(1)-KI mice, but was significantly reduced in mB1-KO animals. Mechanical hyperalgesia induced by injection of the B1 agonist desArg10KD into the contralateral paw 24 h following FCA injection was similar in wild-type and hB1-KI mice, but was absent in mB1-KO animals. Oral administration of NVP-SAA164 produced a dose-related reversal of FCA-induced mechanical hyperalgesia and desArg10KD-induced hyperalgesia in hB1-KI mice, but was inactive against inflammatory pain in wild-type mice. These data demonstrate the use of transgenic technology to investigate the in vivo efficacy of species selective agents and show that NVP-SAA164 is a novel orally active B1 receptor antagonist, providing further support for the utility of B1 receptor antagonists in inflammatory pain conditions in man.
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PMID:Antihyperalgesic activity of a novel nonpeptide bradykinin B1 receptor antagonist in transgenic mice expressing the human B1 receptor. 1568 99

In this study, an extract of Pterocarpus marsupium Roxb. containing pterostilbene has been evaluated for its PGE2-inhibitory activity in LPS-stimulated PBMC. In addition, the COX-1/2 selective inhibitory activity of P. marsupium (PM) extract was investigated. Biological activity, as well as safety of PM extract was evaluated in healthy human volunteers. PM extract, pterostilbene and resveratrol inhibited PGE2 production from LPS-stimulated human peripheral blood mononuclear cells (PBMC) with IC50 values of 3.2 +/- 1.3 microg/mL, 1.0 +/- 0.6 microM and 3.2 +/- 1.4 microM, respectively. When pterostilbene content of PM extract is calculated, PGE2 production inhibition of PM extract is comparable to PGE2 production inhibition of purified pterostilbene. Furthermore, in a COX-1 whole blood assay (WBA) PM extract was not effective while in a COX-2 WBA, PM extract decreased PGE2 production indicating COX-2 specific inhibition. In healthy human volunteers, the oral use of 450 mg PM extract did not decrease PGE2 production ex vivo in a WBA. Pterostilbene levels in serum were increased, but were 5-fold lower than the observed IC50 for PGE2 inhibition in LPS-stimulated PBMC. No changes from base-line of the safety parameters were observed and no extract-related adverse events occurred during the study. In conclusion, this is the first study to describe the selective COX-2 inhibitory activity of a Pterocarpus marsupium extract. Moreover, the PGE2 inhibitory activity of PM extract was related to its pterostilbene content. In humans, 450 mg PM extract resulted in elevated pterostilbene levels in serum, which were below the active concentration observed in vitro. In addition, short-term supplementation of 450 mg PM extract is considered to be a safe dose based on the long history of use, the absence of abnormal blood cell counts and blood chemistry values and the absence of extract-related adverse events. This strongly argues for a dose-finding study of PM extract in humans to corroborate the in vitro observed inhibitory activity on PGE2 production in order to resolve the potential use of PM extract in inflammatory disorders and/or inflammatory pain.
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PMID:Selective COX-2 inhibition by a Pterocarpus marsupium extract characterized by pterostilbene, and its activity in healthy human volunteers. 1593 73

Endotoxin-induced uveitis (EIU) is commonly used in animals to mimic ocular inflammation in humans. Although the peripheral aspects of EIU have been well studied, little is known of the central neural effects of anterior eye inflammation. EIU was induced in male rats by endotoxin or lipopolysaccharide (LPS, 1 mg/kg ip) given 2 or 7 days earlier. Neurons responsive to mechanical stimulation of the ocular surface were recorded under barbiturate anesthesia at the trigeminal subnucleus interpolaris/caudalis (Vi/Vc) transition and subnucleus caudalis/cervical cord (Vc/C1) junction, the main terminal regions for corneal nociceptors. Two days after LPS, Vc/C1 units had reduced responses to histamine, nicotine, and CO(2) gas applied to the ocular surface, whereas unit responses were increased 7 days after LPS. Those units with convergent cutaneous receptive fields at Vc/C1 were enlarged 7 days after LPS. Units at the Vi/Vc transition also had reduced responses to histamine and CO(2) 2 days after LPS but no enhancement was seen at 7 days. Tear volume evoked by CO(2) was reduced 2 days after LPS and returned toward control values by 7 days, whereas CO(2)-evoked eye blinks were normal at 2 days and increased 7 days after LPS. These results indicate that a single exposure to endotoxin causes long-term changes in the excitability of second-order neurons responsive to noxious ocular stimulation. The differential effects of EIU on tear volume and eye blink lend further support for the hypothesis that ocular-sensitive neurons at the Vi/Vc transition and Vc/C1 junction regions mediate different aspects of pain during intraocular inflammation.
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PMID:Endotoxin-induced uveitis causes long-term changes in trigeminal subnucleus caudalis neurons. 1604 40

Preparations of Harpagophytum procumbens, known as devil's claw, are used as an adjunctive therapy for the treatment of pain and osteoarthritis. Pharmacological evaluations have proven the effectiveness of this herbal drug as an anti-inflammatory and analgesic agent. The present study has investigated the mechanism of action of harpagoside, one of the major components of Harpagophytum procumbens, using human HepG2 hepatocarcinoma and RAW 264.7 macrophage cell lines. Harpagoside inhibited lipopolysaccharide-induced mRNA levels and protein expression of cyclooxygenase-2 and inducible nitric oxide in HepG2 cells. These inhibitions appeared to correlate with the suppression of NF-kappaB activation by harpagoside, as pre-treating cells with harpagoside blocked the translocation of NF-kappaB into the nuclear compartments and degradation of the inhibitory subunit IkappaB-alpha. Furthermore, harpagoside dose-dependently inhibited LPS-stimulated NF-kappaB promoter activity in a gene reporter assay in RAW 264.7 cells, indicating that harpagoside interfered with the activation of gene transcription. These results suggest that the inhibition of the expression of cyclooxygenase-2 and inducible nitric oxide by harpagoside involves suppression of NF-kappaB activation, thereby inhibiting downstream inflammation and subsequent pain events.
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PMID:Harpagoside suppresses lipopolysaccharide-induced iNOS and COX-2 expression through inhibition of NF-kappa B activation. 1620 15

Prostaglandin E2 (PGE2) produced by cyclooxygenase-2 (COX-2) and microsomal prostaglandin E2 synthase-1 (mPGES-1) plays an important role in the pathophysiology of inflammation, pain, and fever. We investigated the actions of TNFalpha toward stimulation of PGE2 synthesis in primary spinal cord neurons. TNFalpha induced COX-2 and mPGES-1 expression in neurons, followed by formation of PGE2, which was blocked by a selective COX-2 inhibitor. Surprisingly, the "selective COX-1" inhibitor SC-560 completely inhibited TNFalpha-induced PGE2 synthesis in neurons at nanomolar concentrations. Moreover, SC-560 inhibited PGE2 and thromboxane A2 synthesis in human monocytes and platelets with IC50 of 1.8 nM and 2.5 nM, respectively. SC-560 treatment neither altered TNFalpha-induced COX-2 or mPGES-1 expression nor did the addition of the calcium ionophore A23187 or arachidonic acid reverse the inhibition by SC-560. Moreover, no influence of SC-560 on PGE2 synthase activities or PGE2 transport was seen. Most importantly, SC-560 blocked TNFalpha-induced PGE2 synthesis in COX-1-deficient spinal cord neurons, demonstrating a COX-1-independent inhibition of PGE2 synthesis. Although SC-560 inhibited LPS-induced PGE2 synthesis in neurons and RAW264.7 macrophages in whole cell assays, no inhibition was observed in lysates of the same cells. Taken together our data demonstrate that SC-560 acts at least in some cell types as an unselective COX inhibitor despite its selectivity toward COX-1 under cell-free conditions.
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PMID:Inhibition of prostaglandin E2 synthesis by SC-560 is independent of cyclooxygenase 1 inhibition. 1681 10

Variations in the gene encoding catechol-O-methyltransferase (COMT) are linked to individual differences in pain sensitivity. A single nucleotide polymorphism (SNP) in codon 158 (val(158)met), which affects COMT protein stability, has been associated with the human experience of pain. We recently demonstrated that three common COMT haplotypes, which affect the efficiency of COMT translation, are strongly associated with a global measure of pain sensitivity derived from individuals' responses to noxious thermal, ischemic, and pressure stimuli. Specific haplotypes were associated with low (LPS), average (APS), or high (HPS) pain sensitivity. Although these haplotypes included the val(158)met SNP, a significant association with val(158)met variants was not observed. In the present study, we examined the association between COMT genotype and specific pain-evoking stimuli. Threshold and tolerance to thermal, ischemic, and mechanical stimuli, as well as temporal summation to heat pain, were determined. LPS/LPS homozygotes had the least, APS/APS homozygotes had average, and APS/HPS heterozygotes had the greatest pain responsiveness. Associations were strongest for measures of thermal pain. However, the rate of temporal summation of heat pain did not differ between haplotype combinations. In contrast, the val(158)met genotype was associated with the rate of temporal summation of heat pain, but not with the other pain measures. This suggests that the val(158)met SNP plays a primary role in variation in temporal summation of pain, but that other SNPs of the COMT haplotype exert a greater influence on resting nociceptive sensitivity. Here, we propose a mechanism whereby these two genetic polymorphisms differentially affect pain perception.
Pain 2006 Dec 05
PMID:Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli. 1740 1

Phamacological activities of a standard ethanol extract G1 from Brazilian green propolis, typified as BRP1, was evaluated in mouse models of pain and inflammation. Intraperitoneal injection ( I. P.) of G1 inhibited acetic acid-induced abdominal constrictions with an ID (50) = 0.75 +/- 0.05 mg/kg, and in the formalin test the ID (50) values were 0.85 +/- 0.07 mg/kg and 13.88 +/- 1.12 mg/kg, respectively, for the neurogenic and inflammatory phases. The extract was ineffective when assessed in the hot-plate assay. In serotonin-induced paw edema, G1 led to a maximal inhibition (MI) of 51.6 % after 120 min when administered I. P. and of 36 % after 15 min by the oral route ( O. R.). When the inflammatory agent was complete Freund's adjuvant, inhibition of paw edema was also observed after administration of the extract by both routes. In the capsaicin-induced ear edema the ID (50) values were 1.09 +/- 0.08 mg/kg ( I. P.) and 10.00 +/- 0.90 mg/kg ( O. R.). In the acute carrageenan-induced inflammatory reaction induced by carrageenan, G1 reduced the number of neutrophils in the peritoneal cavity with IC (50) values of 0.72 +/- 0.08 mg/kg and 4.17 +/- 0.50 mg/kg, by I. P. or O. R. administration, with a preferential migration of polymorphonuclear neutrophils. IN VITRO, G1 decreased nitric oxide production in LPS-stimulated RAW 264.7 cells (IC (50) = 41.60 microg/mL), and also the luciferase activity in TNF-alpha-stimulated HEK 293 cells transfected with NF-kappaB-luciferase reporter gene driven by the nuclear factor kappaB (NF-kappaB) (IC (50) = 200 microg/mL). This extract, which at low concentrations induces anti-inflammatory and analgesic effects in mouse models, presents a high content of flavonoids, known to inhibit inducible NOS (iNOS) activity. These data taken together led us to reinforce the hypothesis in the literature that the anti-inflammatory effect of propolis may be a due to inhibition of iNOS gene expression, through interference with NF-kappaB sites in the iNOS promoter.
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PMID:Evaluation of the analgesic and anti-inflammatory effects of a Brazilian green propolis. 1690 58

Lafoensia pacari St. Hil. (Lythraceae) is used in traditional medicine to treat inflammation. Previously, we demonstrated the anti-inflammatory effect that the ethanolic extract of L. pacari has in Toxocara canis infection (a model of systemic eosinophilia). In this study, we tested the anti-inflammatory activity of the same L. pacari extract in mice injected intraperitoneally with beta-glucan present in fraction 1 (F1) of the Histoplasma capsulatum cell wall (a model of acute eosinophilic inflammation). We also determined the anti-oedematous, analgesic and anti-pyretic effects of L. pacari extract in carrageenan-induced paw oedema, acetic acid writhing and LPS-induced fever, respectively. L. pacari extract significantly inhibited leucocyte recruitment into the peritoneal cavity induced by beta-glucan. In addition, the L. pacari extract presented significant analgesic, anti-oedematous and anti-pyretic effects. Bioassay-guided fractionation of the L. pacari extract in the F1 model led us to identify ellagic acid. As did the extract, ellagic acid presented anti-inflammatory, anti-oedematous and analgesic effects. However, ellagic acid had no anti-pyretic effect, suggesting that other compounds present in the plant stem are responsible for this effect. Nevertheless, our results demonstrate potential therapeutic effects of L. pacari extract and ellagic acid, providing new prospects for the development of drugs to treat pain, oedema and inflammation.
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PMID:Anti-inflammatory, analgesic and anti-oedematous effects of Lafoensia pacari extract and ellagic acid. 1694 86

In a prospective randomized double-blind study we compared the postoperative recovery and early results of two groups of 30 patients having total knee arthroplasty with minimally invasive techniques using either a mini-subvastus or a modified "quadriceps-sparing" approach. All knees were implanted with the same posterior-stabilized prosthesis (LPS-Flex, Zimmer, Warsaw, IN) by the same surgeon with the same dedicated set of downsized instruments. Epidural anesthesia with the same postoperative analgesia and rehabilitation protocol was used in all patients. Evaluation was performed preoperatively, postoperatively in the first week, and at 1 and 3 months. In five cases in the "quadriceps- sparing" group, the incision was extended a few cm to facilitate exposure. Tourniquet time, estimated blood loss, and postoperative pain were similar in the two groups. Active straight leg raising was achieved half a day earlier, on average, in the mini-subvastus group (1.9 vs 1.4 days). Average maximum active flexion was similar in the two groups at each interval, and reached 117 degrees and 119 degrees at 3 months for the mini-subvastus and "quadriceps-sparing" group, respectively. We believe there was no difference between the mini-subvastus and "quadriceps-sparing" approach in relation to short term recovery or early results.
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PMID:Quadriceps-sparing versus mini-subvastus approach in total knee arthroplasty. 1695 51


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