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)

The effect of the pro-inflammatory cytokine interleukin-1beta (IL-1beta) on the inducible nitric oxide synthase-nitric oxide (iNOS-NO) cascade in nociceptive signal transduction was examined in the intact rat spinal cord. All rats were implanted with an intrathecal (i.t.) catheter; some were also implanted with an i.t. microdialysis probe. The paw withdrawal latency to radiant heat was used to assess thermal hyperalgesia. The iNOS protein expression in the spinal cord dorsal horn was examined by western blot analysis and NOS activity assay. NO production in the CSF dialysate was also measured. IL-1beta i.t. (100 ng) produced thermal hyperalgesia from 4 to 24 h after i.t. injection. The iNOS protein expression was induced at 4 h after i.t. IL-1beta injection, peaked at the 6th hour, and disappeared at 24 h. The iNOS activity showed a similar time-dependent change as the iNOS protein expression. NO release increased by 1.1- to 1.9-fold between 4 and 12 h, also with a peak at the 6th hour, after i.t. IL-1beta administration. Pretreatment with the iNOS inhibitor 1400W (10 microg, i.t.) 1 h before i.t. IL-1beta injection prevented all the responses of IL-1beta. Neither 1400W nor artificial CSF (aCSF) affected the thermal nociceptive threshold and NO production. These results demonstrate that i.t. administration of IL-1beta induced thermal hyperalgesia by activating the iNOS-NO cascade in the rat spinal cord. On the basis of the present findings, we suggest that i.t. administration of iNOS inhibitors may have potential in the treatment of inflammatory and neuropathic pain syndromes.
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PMID:Intrathecal interleukin-1beta administration induces thermal hyperalgesia by activating inducible nitric oxide synthase expression in the rat spinal cord. 1522 78

Snakebites are a relevant public health problem in Central and South America. Snake bite envenomations cause intense pain, not relieved by anti-venom. The fangs of many species are short, causing subcutaneous injection. Fangs of larger species inflict subcutaneous or intramuscular envenomation. To understand pain induced by subcutaneous venom, this study examined spinal mechanisms involved in pain-enhancing effects of subcutaneous Lys49 and Asp49 secretory phospholipase-A(2) (sPLA2), two components of Bothrops asper snake venom showing highly different enzymatic activities. Unilateral intraplantar sPLA2-Lys49 (catalytically inactive) or sPLA2-Asp49 (catalytically active) into rat hindpaws each induced mechanical hyperalgesia (Randall-Selitto test), whereas only catalytically active sPLA2-Asp49 caused mechanical allodynia (von Frey test). Effects induced by both sPLA2s were inhibited by intrathecal fluorocitrate, a reversible glial metabolic inhibitor. In support, immunohistochemical analysis revealed activation of dorsal horn astrocytes and microglia after intraplantar injection of either sPLA2. Spinal proinflammatory cytokines, nitric oxide, and prostanoids each appear to be involved in the pain-enhancing effects of these sPLA2s. Blockade of interleukin-1 (IL1) inhibited hyperalgesia induced by both sPLA2s, while leaving allodynia unaffected. Blockade of tumor necrosis factor reduced responses to sPLA2-Asp49. An inhibitor of neuronal nitric oxide synthase, 7-nitroindazole (7-NI), inhibited hyperalgesia induced by both sPLA2s, without interfering with allodynia induced by sPLA2-Asp49. On the other hand, L-N(6)-(1-iminoethyl)lysine (L-NI), an inhibitor of the inducible nitric oxide synthase, did not alter any sPLA2-induced effect. Lastly, celecoxib, an inhibitor of cyclooxygenase-2, attenuated sPLA2 actions. These data provide the first evidence of spinal mediators involved in pain facilitation induced by subcutaneous venoms.
Pain 2004 Sep
PMID:Snake venom components enhance pain upon subcutaneous injection: an initial examination of spinal cord mediators. 1532 10

Dioscoreae Rhizoma (MDR), the root of Dioscorea tokoro MAKINO, has been used for the treatment of arthritis, muscular pain and urinary diseases in oriental medicine. The present work evaluates a methanol extract of Dioscoreae Rhizoma (MDR). MDR did not show any cytotoxic effect on mouse lung fibroblast cells (mLFCs) or human fibroblast-like synovial cells (hFLSCs). However, it significantly reduced the proliferation of hFLSCs stimulated by interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). MDR significantly inhibited the production of TNF-alpha and IL-1beta as well as down-regulating the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in IL-1beta- and TNF-alpha-stimulated hFLSCs. MDR also effectively reduced the level of reactive oxygen species (ROS) in these cells. Taken together, these findings provide evidence that MDR may be a candidate for the treatment of rheumatoid arthritis (RA).
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PMID:Methanol extract of Dioscoreae Rhizoma inhibits pro-inflammatory cytokines and mediators in the synoviocytes of rheumatoid arthritis. 1535 18

Armeniacae semen is the seed of Prunus armeniaca L. var. ansu MAXIM which is classified into Rosaceae. In traditional oriental medicine, Armeniacae semen has been used for the treatment of pain and inflammatory diseases. In this study, the effect of Armeniacae semen extract on lipopolysaccharide-induced inflammation was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, reverse transcription-polymerase chain reaction (RT-PCR), Western blot, prostaglandin E2 immunoassay, and nitric oxide detection on mouse BV2 microglial cells. In the present results, Armeniacae semen extract suppressed prostaglandin E2 synthesis and nitric oxide production by inhibiting the lipopolysaccharide-stimulated enhancement of cyclooxygenase-2 and inducible nitric oxide synthase mRNA expression in BV2 cells. These results show that Armeniacae semen exerts anti-inflammatory and analgesic effects probably by suppression of cyclooxygenase-2 and inducible nitric oxide synthase expressions.
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PMID:Armeniacae semen extract suppresses lipopolysaccharide-induced expressions of cyclooxygenase [correction of cycloosygenase]-2 and inducible nitric oxide synthase in mouse BV2 microglial cells. 1574 67

Opioids are sometimes used to treat pain in ulcerative wounds, and it is speculated that pain interferes with the healing process. Because the direct effect of opioids on this process remains unknown, we examined the effect of topically applied opioids on the healing of open ischemic wounds in rats. Topically applied opioids hastened wound closure, particularly in the first 4 days when no healing was initiated in phosphate buffered saline solution-treated wounds. After 1 week of application, fentanyl, hydromorphone, and morphine resulted in 66%, 55%, and 42% wound closure, respectively, as compared to only 15% in control wounds. Opioid-induced healing was accompanied by a 1.5- to 2.5-fold increase in nuclear density in the granulation tissue and 45-87% increase in angiogenesis as compared to phosphate buffered saline solution-treated wounds. Fentanyl showed significantly improved healing compared to morphine and hydromorphone (p < 0.05, fentanyl vs. others). Fentanyl-induced healing was inhibited by the opioid receptor antagonist naloxone, suggesting that peripheral opioid receptor(s) mediate the healing process. Opioids accelerate healing by up-regulating both endothelial and inducible nitric oxide synthase and the vascular endothelial-derived growth factor receptor Flk1 in the wounds. We envision that opioids can be used topically to accelerate wound healing in diverse clinical conditions ranging from surgical incisions to nonhealing ischemic ulcers in pathophysiological conditions and in hospice patients.
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PMID:Opioids heal ischemic wounds in the rat. 1582 41

Nitric oxide generated by the nitric oxide synthase (NOS) isoforms contributes to pain processing. The selective inhibition of iNOS might represent a novel, therapeutic target for the development of antinociceptive compounds. However, few isoform-selective inhibitors of NOS have been developed. The present experiments examined the anti-inflammatory and antinociceptive activity of a selective inducible nitric oxide (iNOS) inhibitor, AR-C102222, on arachidonic acid-induced ear inflammation, Freund's complete adjuvant (FCA)-induced hyperalgesia, acetic acid-induced writhing, and tactile allodynia produced by L5 spinal nerve ligation (L5 SNL) or hindpaw incision (INC). AR-C102222 at a dose of 100mg/kg p.o., significantly reduced inflammation produced by the application of arachidonic acid to the ear, attenuated FCA-induced mechanical hyperalgesia, and attenuated acetic acid-induced writhing. In the L5 SNL and INC surgical procedures, tactile allodynia produced by both procedures was significantly reduced by 30mg/kg i.p. of AR-C102222. These data demonstrate that the selective inhibition of iNOS produces antinociception in different models of pain and suggest that the iNOS-NO system plays a role in pain processing.
Eur J Pain 2006 Aug
PMID:Antinociceptive activity of the selective iNOS inhibitor AR-C102222 in rodent models of inflammatory, neuropathic and post-operative pain. 1612 26

Clinically, inflammatory pain is far more persistent than that typically modelled pre-clinically, with the majority of animal models focussing on short-term effects of the inflammatory pain response. The large attrition rate of compounds in the clinic which show pre-clinical efficacy suggests the need for novel models of, or approaches to, chronic inflammatory pain if novel mechanisms are to make it to the market. A model in which a more chronic inflammatory hypersensitivity phenotype is profiled may allow for a more clinically predictive tool. The aims of these studies were to characterise and validate a chronic model of inflammatory pain. We have shown that injection of a large volume of adjuvant to the intra-articular space of the rat knee results in a prolonged inflammatory pain response, compared to the response in an acute adjuvant model. Additionally, this model also results in a hypersensitive state in the presence and absence of inflammation. A range of clinically effective analgesics demonstrate activity in this chronic model, including morphine (3mg/kg, t.i.d.), dexamethasone (1mg/kg, b.i.d.), ibuprofen (30mg/kg, t.i.d.), etoricoxib (5mg/kg, b.i.d.) and rofecoxib (0.3-10mg/kg, b.i.d.). A further aim was to exemplify the utility of this chronic model over the more acute intra-plantar adjuvant model using two novel therapeutic approaches; NR2B selective NMDA receptor antagonism and iNOS inhibition. Our data shows that different effects were observed with these therapies when comparing the acute model with the model of chronic inflammatory joint pain. These data suggest that the chronic model may be more relevant to identifying mechanisms for the treatment of chronic inflammatory pain states in the clinic.
Eur J Pain 2006 Aug
PMID:An animal model of chronic inflammatory pain: pharmacological and temporal differentiation from acute models. 1619 87

Nitric oxide (NO) is synthesized in large quantities by activated inflammatory cells and has been demonstrated to be involved in the pathogenesis of acute and chronic inflammatory conditions. Seabuckthorn (SBT) has been used in traditional medicine systems for the treatment of various diseases like cardiovascular, pain relief, oral inflammation and promotion of tissue regeneration. The present study focuses on the effects of SBT leaf extract on NO production induced by lipopolysaccharide (LPS) in the murine macrophage cell line RAW 264.7. In addition, cell viability, free radical-scavenging activity and inducible nitric oxide synthase (iNOS) expression were also evaluated. Seabuckthorn leaf extract significantly inhibited the enhanced production of NO induced by LPS in a dose dependent manner. Treatment with SBT did not reduce cell viability at any dose used. The extract showed significant scavenging of NO radicals released by the NO donor. Treatment of macrophages with SBT leaf extract also caused a significant inhibition of iNOS activation. These observations suggest that the inhibition of net NO production by SBT leaf extract may be due to its scavenging activity and/or its inhibitory effects on iNOS activation. The study suggests that SBT leaf extract has significant anti-inflammatory activity and has potential for the treatment of inflammatory diseases.
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PMID:Effect of leaf extract of Seabuckthorn on lipopolysaccharide induced inflammatory response in murine macrophages. 1633 12

Nitric oxide (NO), synthesised by different isoforms of nitric oxide synthase (NOS), has been linked with the development and maintenance of nociception. We studied the role of the inducible isoform, iNOS, in two different rat pain models with an inflammatory component. iNOS was immunohistochemically detected locally in the paw 6h after Freund's Complete Adjuvant (FCA) injection, showing a plateau at 24-72 h and falling slowly in the following weeks. This correlated with the late phase of the hypersensitivity to pain revealed in the behavioural tests. A highly selective iNOS inhibitor GW274150 (1-30 mg/kg orally, 24h after FCA) suppressed the accumulation of nitrite in the inflamed paw indicating substantial iNOS inhibition. At the same time it partially reversed FCA-induced hypersensitivity to pain and edema in a dose-dependent manner. After Chronic Constriction Injury (CCI) surgery to the sciatic nerve, iNOS presence was only detected locally in the region of the nerve (inflammatory cells). GW274150 (3-30 mg/kg orally, 21 days after surgery) also reversed significantly the CCI-associated hypersensitivity to pain. No iNOS was detectable in dorsal root ganglia, spinal cord or brain in either model. This study demonstrates a role for peripherally-expressed iNOS in pain conditions with an inflammatory component and the potential value of iNOS inhibitors in such conditions.
Pain 2006 Jan
PMID:GW274150, a novel and highly selective inhibitor of the inducible isoform of nitric oxide synthase (iNOS), shows analgesic effects in rat models of inflammatory and neuropathic pain. 1636 Feb 70

Nitric oxide (NO) is an important signalling molecule that has been suggested to be a key molecule for induction and maintenance of migraine attacks based on clinical studies, animal experimental studies and the expression of nitric oxide synthase (NOS) immunoreactivity within the trigeminovascular system. Sensitisation of the trigeminal system including the trigeminal ganglia neurones is believed to be involved in the pathway leading to migraine pain. In the present study, the NOS expression in rat primary trigeminal ganglia neurones was examined at different time points using immunocytochemistry, reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting. In trigeminal ganglia cells not subjected to culture, endothelial (e) and neuronal (n) but not inducible (i) NOS mRNA and protein were detected. Culture of rat neurones resulted in a rapid axonal outgrowth of NOS positive fibres. At 12, 24 and 48 hr of culture, NOS immunoreactivity was detected in medium-sized trigeminal ganglia cells. Western blotting and RT-PCR revealed an up-regulation of inducible iNOS expression during culture. However, after culture only low levels of eNOS protein was found while no eNOS and nNOS mRNA and protein could be detected. The data suggest that iNOS expression may be a molecular mechanism mediating the adaptive response of trigeminal ganglia cells to the serum free stressful stimulus the culture environment provides. It may act as a cellular signalling molecule that is expressed after cell activation.
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PMID:Expression of inducible nitric oxide synthase in trigeminal ganglion cells during culture. 1636 50


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