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)

Nerve injury may result in neuropathic pain, characterized by allodynia and hyperalgesia. Accumulating evidence suggests the existence of a molecular substrate for neuropathic pain produced by neurons, glia, and immune cells. Here, we show that leptin, an adipokine exclusively produced by adipocytes, is critical for the development of tactile allodynia through macrophage activation in mice with partial sciatic nerve ligation (PSL). PSL increased leptin expression in adipocytes distributed at the epineurium of the injured sciatic nerve (SCN). Leptin-deficient animals, ob/ob mice, showed an absence of PSL-induced tactile allodynia, which was reversed by the administration of leptin to the injured SCN. Perineural injection of a neutralizing antibody against leptin reproduced this attenuation. Macrophages recruited to the perineurium of the SCN expressed the leptin receptor and phosphorylated signal transducer and activator of transcription 3 (pSTAT3), a transcription factor downstream of leptin. PSL also up-regulated the accepted mediators of neuropathic pain--namely, cyclooxygenase-2, inducible nitric oxide synthase, and matrix metalloprotease-9--in the injured SCN, with transcriptional activation of their gene promoters by pSTAT3. This up-regulation was partly reproduced in a macrophage cell line treated with leptin. Administration of peritoneal macrophages treated with leptin to the injured SCN reversed the failure of ob/ob mice to develop PSL-induced tactile allodynia. We suggest that leptin induces recruited macrophages to produce pronociceptive mediators for the development of tactile allodynia. This report shows that adipocytes associated with primary afferent neurons may be involved in the development of neuropathic pain through adipokine secretion.
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PMID:Leptin derived from adipocytes in injured peripheral nerves facilitates development of neuropathic pain via macrophage stimulation. 1962 Jul 23

This study examined the analgesic and anti-inflammatory actions of cis-mulberroside A isolated from Ramulus mori in several models of inflammatory pain in mice. Cis-mulberroside A (25 and 50mg/kg) given by p.o. route 30 min before challenge produced a dose-dependent inhibition of the acetic acid-induced pain and Evans blue leakage in mice. In addition, this compound exhibited significant systemic anti-inflammatory activity in carrageenan-induced mouse paw edema in a concentration-related manner (33.1-68.5% inhibition), and similar results were achieved in formalin test. Suppressive effects of cis-mulberroside A on the production of NO and expression of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-stimulated macrophages were also assessed. Collectively, cis-mulberroside A showed high analgesic and anti-inflammatory activities. The above results will be the supporting evidence for the potential anti-rheumatoid activity of R.mori in Chinese traditional medicine.
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PMID:Anti-inflammatory and analgesic properties of cis-mulberroside A from Ramulus mori. 1975 40

Most chronic neck pain is the result of degeneration of the cervical spine. IL-1beta may play an important role in intervertebral disc degeneration. This being the case, inhibiting IL-1beta could provide a therapeutic approach for reducing or preventing disc degeneration. Muscone reportedly relieves pain and suppresses inflammation. Therefore, we asked whether muscone, a potent antiinflammatory agent, could reduce proinflammatory cytokines in vitro (end-plate cartilage cultures) and end-plate degeneration in vivo (a rat model that induces intervertebral disc degeneration). In vitro, muscone reversed IL-1beta-induced upregulation of IL-1beta, tumor necrosis factor alpha, cyclooxygenase 2, inducible nitric oxide synthase, matrix metalloproteinase 13, aggrecanase 2, and nitric oxide and downregulation of Col2alpha1 and aggrecan. Pretreatment with muscone (6.25, 12.5, 25 mumol/L) inhibited the IL-1beta-induced phosphorylation of extracellular signal-regulated kinases 1/2 and c-Jun N-terminal kinase in a dose-dependent manner. In vivo, muscone inhibited the expression of prostaglandin E2, 6-keto-prostaglandin F1alpha, IL-1beta, and tumor necrosis factor alpha and recovered the structural distortion of the degenerative disc. Our findings suggest muscone is a promising agent for treating intervertebral disc degeneration through its antiinflammatory effects.
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PMID:Muscone protects vertebral end-plate degeneration by antiinflammatory property. 1976 23

In order to investigate a putative role for nitric oxide (NO) in the central nociceptive processing following carrageenan-induced arthritis in the rat temporomandibular joint (TMJ), we analyzed the immunoreactivity, gene expression and activity of nitric oxide synthases (NOS) in the caudal part of the spinal trigeminal nucleus (Sp5C) during the acute (24 h), chronic (15 days) and chronic-active (14 days-24 h) arthritis. In addition, evaluation of head-withdrawal threshold was carried out in all phases of arthritis under chronic inhibition of nNOS with the selective inhibitor 7-nitroindazole (7-NI). Neurons with nNOS-like immunoreactivity (nNOS-LI) were concentrated mainly in the lamina II of the Sp5C, showing no significant statistical difference during arthritis. Only a discrete percentage of nNOS-LI neurons expressed Fos immunoreactivity. The mRNA expression for both nNOS and endothelial nitric oxide synthases (eNOS) presented no noticeable differences among the groups. No expression of inducible nitric oxide synthase (iNOS) was detected in the Sp5C by either immunohistochemistry or reverse-transcription polymerase chain reaction (RT-PCR). Ca(2+)-dependent NOS activity in the ipsilateral Sp5C was significantly higher (108.3+/-49.2%; P<0.01) in animals during the chronic arthritis. Interestingly, this increased activity was completely abolished 24 h later, in the chronic-active arthritis. Finally, head-withdrawal threshold decreased significantly in the chronic arthritis in animals under 7-NI chronic inhibition. In conclusion, nNOS immunoreactivity and mRNA expression are stable in the Sp5C during TMJ arthritis evolution, but its activity significantly increases in the chronic-phases supporting an antinociceptive role of the nNOS as evidenced by pain threshold experiment.
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PMID:Putative antinociceptive action of nitric oxide in the caudal part of the spinal trigeminal nucleus during chronic carrageenan-induced arthritis in the rat temporomandibular joint. 1976 51

Src-suppressed C kinase substrate (SSeCKS), is an in vivo and in vitro protein kinase C substrate that may have a role in both mitogenic regulation and cytoskeletal arrangement. In this study, we mainly investigated the mRNA and protein expression and cellular localization of SSeCKS during chronic constriction injury (CCI). Reverse transcriptase-mediated PCR and western blot analysis revealed that SSeCKS was present in normal whole spinal cord. It gradually increased, and reached a peak at 2 weeks for its mRNA level and 7 days for its protein level after CCI. The protein expression of SSeCKS was further analyzed by immunohistochemistry. The positively stained areas for SSeCKS changed with the similar pattern to that of protein expression detected by immunoblotting analysis. Double immunofluorescence staining showed SSeCKS immunoreactivity was mostly co-localized with neurons, partly with activated astrocytes and rarely with microglia in the superficial laminar of spinal dorsal horn. In cell culture, the expression of pro-inflammation cytokines, p-ERK, and SSeCKS was increased in the spinal astrocytes after stimulated by damaged sensory neurons. However, SSeCKS gene silencing by siRNA inhibited the up-regulation of p-ERK and the pro-inflammation cytokines. Taken together, activated astrocytes released cytokines and iNOS after neuropathic pain via SSeCKS-ERK signaling. SSeCKS might be critical for the activation of astrocytes in the neuropathic pain.
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PMID:A critical role of SRC-suppressed C kinase substrate in rat astrocytes after chronic constriction injury. 1993 3

Nitric oxide (NO) is a versatile messenger molecule first associated with endothelial relaxing effects. In the central nervous system (CNS), NO synthesis is primarily triggered by activation of N-methyl-D-aspartate (NMDA) receptors and has a Janus face, with both beneficial and harmful properties. There are three isoforms of the NO synthesizing enzyme nitric oxide synthase (NOS): neuronal (nNOS), endothelial (eNOS), and inducible nitric oxide synthase (iNOS), each one involved with specific events in the brain. In the CNS, nNOS is involved with modulation of synaptic transmission through long-term potentiation in several regions, including nociceptive circuits in the spinal cord. Here, we review the role played by NO on central pain sensitization.
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PMID:Pain modulation by nitric oxide in the spinal cord. 2001 Nov 39

Kinins are vasoactive peptides that play important roles in cardiovascular homeostasis, pain and inflammation. After release from their precursor kininogens, kinins or their C-terminal des-Arg metabolites activate two distinct G protein-coupled receptors (GPCR), called B2 (B2R) or B1 (B1R). The B2R is expressed constitutively with a wide tissue distribution. In contrast, the B1R is not expressed under normal conditions but is upregulated by tissue insult or inflammatory mediators. The B2R is considered to mediate many of the acute effects of kinins while the B1R is more responsible for chronic responses in inflammation. Both receptors can couple to Galphai and Galphaq families of G proteins to release mediators such as nitric oxide (NO), arachidonic acid, prostaglandins, leukotrienes and endothelium-derived hyperpolarizing factor and can induce the release of other inflammatory agents. The focus of this review is on the different transduction events that take place upon B2R and B1R activation in human endothelial cells that leads to generation of NO via activation of different NOS isoforms. Importantly, B2R-mediated eNOS activation leads to a transient ( approximately 5min) output of NO in control endothelial cells whereas in cytokine-treated endothelial cells, B1R activation leads to very high and prolonged ( approximately 90min) NO production that is mediated by a novel signal transduction pathway leading to post-translational activation of iNOS.
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PMID:Differential regulation of inducible and endothelial nitric oxide synthase by kinin B1 and B2 receptors. 2004 58

Temporomandibular joint disorders (TMD) show complex symptoms associated with inflammation, pain and degeneration of the peripheral tissues including synovium. Although it is believed that excessive mechanical stress on synovium causes development of TMD, the molecular mechanism by which mechanical stress triggers TMD has still remained unclear. In order to examine the effect of mechanical stress on synoviocytes, rabbit synovial cells were cyclically stretched in vitro. The stretch efficiently increased the gene expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and NF-kappaB responsive reporter gene constructs. The interruption of NF-kappaB activating pathway by inhibitors resulted in the abrogation of those expressions, indicating the pivotal role of NF-kappaB in the mechanical stretch-mediated COX-2 and iNOS expressions. In parallel, the stretch remarkably increased NO production and poly(ADP-ribose) (PAR) synthesis, suggesting that excessive amounts of NO causes DNA injury and in turn activates PAR synthesis by poly(ADP-ribose) polymerase (PARP). The inhibition of PAR synthesis by a PARP inhibitor or a radical scavenger enhanced the mechanical stretch-induced gene expressions in a NF-kappaB-independent manner, implying an involvement of PARP in the gene expression. Taken together, these results demonstrate that mechanical stress on synovial cells not only induces gene expressions of COX-2 and iNOS but also affects PAR synthesis.
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PMID:Mechanical stretch enhances NF-kappaB-dependent gene expression and poly(ADP-ribose) synthesis in synovial cells. 2005 85

This study is to explore the effects of extracts of Cheezheng pain relieving plaster (ECPRP) on nitric oxide (NO) production and expression of inducible nitric oxide synthase (iNOS) in macrophages induced by LPS and the mechanism involved. Nitric oxide level was measured with Griess reagent assay. Inducible nitric oxide synthase (iNOS) protein and NF-kappaBp65 fragment were detected with Western blotting. ECPRP (62.5 and 125 mgL(-1)) significantly inhibited the increase of nitric oxide level. Furthermore, ECPRP (62.5 and 125 mg x L(-1)) notably reduced the expression of iNOS mRNA and protein. ECPRP (62.5 and 125 mg x L(-1)) elevated the content of I-kappaB protein in cytoplasm, while decreased the content of NF-kappaBp65 protein in nucleus. These results suggest that ECPRP reduce nitric oxide level via down-regulation of NF-kappaB-iNOS-nitric oxide pathway, resulting in prevention of inflammation.
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PMID:[Effects of extracts of cheezheng pain relieving plaster on nitric oxide and iNOS expression in macrophages induced by lipopolysaccharides]. 2005 53

Ergostatrien-3beta-ol (ST1), an active and major ingredient from Antrodia camphorata (AC) submerged whole broth was evaluated for the analgesic and anti-inflammatory effects. Treatment of male imprinting control region (ICR) mice with ST1 (1, 5, and 10 mg/kg) significantly inhibited the numbers of acetic-acid-induced writhing response in 10 min. Also, our result showed that ST1 (10 mg/kg) significantly inhibited the formalin-induced pain in the late phase (p < 0.001). In the anti-inflammatory test, ST1 (10 mg/kg) decreased the paw edema at 4 and 5 h after lambda-carrageenin (Carr) administration and increased the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in the liver tissue. We also demonstrated that ST1 significantly attenuated the malondialdehyde (MDA) level in the edema paw at 5 h after Carr injection. ST1 (1, 5, and 10 mg/kg) decreased the nitric oxide (NO) levels on both the edema paw and serum level at 5 h after Carr injection. Also, ST1 (5 and 10 mg/kg) diminished the serum tumor necrosis factor (TNF-alpha) at 5 h after Carr injection. Western blotting revealed that ST1 (10 mg/kg) decreased Carr-induced inducible nitric oxide synthase (iNOS), and cycloxyclase (COX-2) expressions at 5 h in the edema paw. An intraperitoneal (ip) injection treatment with ST1 also diminished neutrophil infiltration into sites of inflammation, as did indomethacin (Indo). The anti-inflammatory mechanisms of ST1 might be related to the decrease in the level of MDA, iNOS, and COX-2 in the edema paw via increasing the activities of CAT, SOD, and GPx in the liver through the suppression of TNF-alpha and NO.
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PMID:Analgesic effects and the mechanisms of anti-inflammation of ergostatrien-3beta-ol from Antrodia camphorata submerged whole broth in mice. 2050 40


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