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)

Tumor necrosis factor-alpha (TNF) is involved in the generation of inflammatory and neuropathic pain. The synthetic hydroxamic acid based metalloprotease inhibitor TAPI blocks cleavage of cell surface TNF and thus reduces levels of the mature 17-kDa TNF polypeptide in activated macrophages and T-cells. We have previously shown that pharmacologic inhibition of TNF production reduces pain related behaviors in mice with chronic constriction injury (CCI). Here we investigated whether blockage of TNF shedding by administration of TAPI would diminish hyperalgesia in animals with partial nerve injury. We injected 0.5 mg of the inhibitor epineurially once daily to mice with CCI for 7 days. The animals were tested for withdrawal thresholds to heat to test for thermal hyperalgesia and to von Frey hairs to assess mechanical allodynia. Mice with CCI developed thermal hyperalgesia and mechanical allodynia by day 3 after the injury. In mice treated with TAPI, a reduction of thermal hyperalgesia and mechanical allodynia of up to 50% occurred. Endoneurial TNF-immunoreactivity was reduced, but not immunoreactivity for IL-1alpha or IL-1beta. The numbers of degenerating axons and endoneurial macrophages were not affected by the treatment as compared to controls. We conclude that the metalloprotease inhibitor TAPI specifically reduces endoneurial TNF-levels after nerve injury and thereby may diminish neuropathic pain in the CCI-model.
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PMID:A metalloprotease-inhibitor reduces pain associated behavior in mice with experimental neuropathy. 940 76

Tumor necrosis factor-alpha (TNF-alpha) is a key player in peripheral nerve injury. In the inflammatory chronic constriction injury (CCI) model of sciatic neuropathy, upregulation of TNF-alpha mRNA and protein at the site of nerve injury has been associated with pain. We now report the distribution of endogenous TNF-alpha protein and its receptors along normal and CCI-injured sciatic nerves, and within the corresponding lumbar dorsal root ganglia (DRG). Using Western blotting, TNF-alpha was found to be distinctly increased at the injury site, as well as in the axons just distal to the corresponding DRG. The TNF-alpha signal between the injury site and DRG (midaxonal) was induced between 2 and 5 days post-CCI, suggesting activation of TNF-alpha axonal transport. Endogenous TNF-alpha was localized in small-diameter, presumably nociceptive, and large-diameter, presumably mechanoceptive, DRG sensory neurons in both normal and CCI animals. Intraneural microinjection of biotin-labeled TNF-alpha showed specific axonal uptake at the injection site, as detected by avidin-biotin-peroxidase histochemistry, and confirmed by co-localization with neurobiotin tracer. In control animals, fast retrograde transport of biotinylated TNF-alpha to both L4 and L5 DRG neurons was apparent 6 h following injection. TNF receptors TNFRI and TNFRII co-localized with biotinylated TNF-alpha tracer along the nerve trunk, suggesting that TNF-alpha transport may be receptor-mediated. In animals with CCI neuropathy, uptake of biotinylated TNF-alpha by neuronal soma was inhibited. Instead, there was signal accumulation in the axons immediately distal to the DRG, and TNFRI and RII were increased at this same anatomic location. These findings highlight a dynamic process of TNF-alpha protein and receptor regulation throughout the peripheral neural axis that bears on both the normal function of DRG neurons and the pathogenesis of painful neuropathies.
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PMID:Axonal transport of TNF-alpha in painful neuropathy: distribution of ligand tracer and TNF receptors. 1124 15

Tumor necrosis factor-alpha (TNF) appears as a key player at both central and peripheral terminals in early degenerative pathology and pain behavior after peripheral nerve injury. Recent studies suggest that TNF may be axonally transported and thereby contribute to these central and peripheral actions. To characterize this transport, we used a double ligation (DL) procedure that distinguishes between anterograde and retrograde flow to visualize the axonal transport of endogenous TNF compared with the neurotrophin nerve growth factor (NGF) and to the neuropeptide calcitonin gene-related peptide (CGRP). In the intact nerve, TNF and CGRP immunoreactivity predominantly accumulated proximal to the DL (anterograde transport), whereas NGF displayed exclusive retrograde transport. At 20 hr after chronic constrictive injury (CCI), the anterograde transport of TNF and CGRP to the nerve injury site was dramatically increased. The results were corroborated by the analysis of axonal transport of exogenously applied 125I-TNF and 125I-NGF. After intraneural injection, 125I-TNF accumulated proximally to a DL, suggesting anterograde transport. In the unligated nerve, 125I-TNF was specifically transported anterogradely to the innervated muscle but not to skin. After CCI, 125I-TNF accumulated proximally to the peripheral nerve injury site, and endogenous TNF was exclusively increased in medium-sized and large dorsal root ganglion (DRG) neurons, suggesting that DRG neurons are a major contributing source of increased TNF traffic in the injured sciatic nerve. Our results suggest that anterograde transport of TNF plays a major role in the early neuronal response to peripheral nerve injury at sites distal to the cell body.
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PMID:Anterograde transport of tumor necrosis factor-alpha in the intact and injured rat sciatic nerve. 1178

Rheumatoid arthritis is a debilitating, chronic, systemic, autoimmune disease of unknown etiology that causes destruction of joint cartilage and bone. It generally occurs between the fourth and sixth decades of life, and affects two to three times more women than men. It is characterized by joint stiffness, pain, and swelling, and is accompanied by a loss of body cell mass. This loss of cell mass, known as rheumatoid cachexia, predominates in skeletal muscle, but also occurs in the viscera and immune system. Thus, rheumatoid cachexia leads to muscle weakness and a loss of functional capacity, and is believed to accelerate morbidity and mortality in rheumatoid arthritis. Currently there is no established mechanism for rheumatoid cachexia, but it is accompanied by elevated resting energy expenditure, accelerated whole-body protein catabolism, and excess production of the inflammatory cytokines, tumor necrosis factor-alpha and interleukin-1beta. Tumor necrosis factor-alpha is probably the central mediator of muscle wasting in rheumatoid arthritis, and is known to act synergistically with interleukin-1beta to promote cachexia. In general, tumor necrosis factor-alpha and interleukin-1beta are thought to alter the balance between protein degradation and protein synthesis in rheumatoid arthritis to cause muscle wasting. The precise mechanism by which they do this is not known. Reduced peripheral insulin action and low habitual physical activity are important consequences of rheumatoid arthritis, and have also been implicated as mediators of rheumatoid cachexia. Insulin inhibits muscle protein degradation. Consequently, reduced peripheral insulin action in rheumatoid arthritis is thought to be permissive to cytokine-driven muscle loss. The cause of reduced peripheral insulin action in rheumatoid arthritis is not known, but tumor necrosis factor-alpha has been shown to interfere with insulin receptor signaling and is probably an important contributor. Low habitual physical activity has consistently been observed in rheumatoid arthritis and is an important consequence of, and contributor to, muscle wasting. In addition, low physical activity predisposes to fat gain and is believed to precipitate a negative reinforcing cycle of muscle loss, reduced physical function, and fat gain in rheumatoid arthritis, which leads to 'cachectic obesity'. To date, there is no standard treatment for rheumatoid cachexia. However, physical exercise is currently believed to be the most important and clinically relevant countermeasure against rheumatoid cachexia. In general, a combination of skeletal muscle strength training and aerobic exercise is recommended, but must be prescribed with the patient's disease status, overall health, and safety in mind. Future studies should investigate the safety, efficacy, and required dose of anti-cytokine therapy for the treatment of rheumatoid cachexia. In this review, we outline the current definition of rheumatoid cachexia, and discuss the etiology, pathogenesis, and treatment of rheumatoid cachexia.
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PMID:Cachexia in rheumatoid arthritis. 1216 13

Tumor necrosis factor-alpha (TNF) is implicated in the initiation of neuropathic pain. In vitro, TNF activates p38 mitogen-activated kinase. Accordingly, we investigated whether TNF activates the p38 cascade in vivo to trigger pain behavior after spinal nerve ligation (SNL). Treatment starting 2 d before SNL with the TNF antagonist etanercept (1 mg, i.p., every third day) attenuated mechanical allodynia. Treatment starting 1 or 7 d after SNL was ineffective. Similarly, intrathecal infusion of a p38 inhibitor (SB203580, 4 mg/d) was effective only if it was started before but not 7 d after SNL. For both treatments, the cessation of therapy resulted in increased allodynia. In separate experiments using Western blots and immunohistochemistry, ipsilateral lumbar spinal cord and L5 and L6 DRG were analyzed for total and phosphorylated p38 after SNL alone or SNL combined with etanercept pretreatment. In DRG, activated p38 was transiently elevated 5 hr after SNL and returned to baseline by 1 d after SNL. Phosphorylated p38 was localized in small TNF-positive DRG neurons. In spinal cord, p38 was activated between 5 hr and 3 d after SNL and returned to baseline within 5 d. In DRG, but not spinal cord, etanercept pretreatment blocked p38 activation. These data indicate that after SNL treatment, phosphorylated p38 levels in spinal cord and DRG are transiently elevated. In DRG, p38 activation is blocked by systemic TNF inhibition. Parallel inhibition of p38 activation and allodynia may represent a clinically relevant therapeutic window. These data suggest a sequential role for TNF and p38 in the induction of neuropathic pain.
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PMID:Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. 1268 35

Tumor necrosis factor-alpha (TNF) is upregulated after nerve injury, causes pain on injection, and its blockade reduces pain behavior resulting from nerve injury; thus it is strongly implicated in neuropathic pain. We investigated responses of intact and nerve-injured dorsal root ganglia (DRG) neurons to locally applied TNF using parallel in vivo and in vitro paradigms. In vivo, TNF (0.1-10 pg/ml) or vehicle was injected into L5 DRG in naive rats and in rats that had received L5 and L6 spinal nerve ligation (SNL) immediately before injection. In naive rats, TNF, but not vehicle, elicited long-lasting allodynia. In SNL rats, subthreshold doses of TNF synergized with nerve injury to elicit faster onset of allodynia and spontaneous pain behavior. Tactile allodynia was present in both injured and adjacent uninjured (L4) dermatomes. Preemptive treatment with the TNF antagonist etanercept reduced SNL-induced allodynia by almost 50%. In vitro, the electrophysiological responses of naive, SNL-injured, or adjacent uninjured DRG to TNF (0.1-1000 pg/ml) were assessed by single-fiber recordings of teased dorsal root microfilaments. In vitro perfusion of TNF (100-1000 pg/ml) to naive DRG evoked short-lasting neuronal discharges. In injured DRG, TNF, at much lower concentrations, elicited earlier onset, markedly higher, and longer-lasting discharges. TNF concentrations that were subthreshold in naive DRG also elicited high-frequency discharges when applied to uninjured, adjacent DRG. We conclude that injured and adjacent uninjured DRG neurons are sensitized to TNF after SNL. Sensitization to endogenous TNF may be essential for the development and maintenance of neuropathic pain.
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PMID:Increased sensitivity of injured and adjacent uninjured rat primary sensory neurons to exogenous tumor necrosis factor-alpha after spinal nerve ligation. 1268 90

Carrageenan-induced inflammatory pain lasting hours to days produces a protein kinase C epsilon (PKC epsilon )-dependent 'primed' state lasting several weeks, during which time injection of prostaglandin E2 induces hyperalgesia which is markedly enhanced and prolonged compared to PGE2-induced hyperalgesia in normal 'unprimed' rats. In the present study, we demonstrate that while inhibition of prostaglandin synthesis and antagonism of beta2-adrenergic receptors markedly attenuated the hyperalgesia induced by carrageenan, these interventions did not affect hyperalgesic priming. Tumor necrosis factor-alpha (rat recombinant; rrTNFalpha), another mediator of carrageenan-induced inflammation, alone produced hyperalgesia and priming, which were attenuated and prevented, respectively, by intrathecal administration of antisense to PKC epsilon. Inhibition of TNFalpha with thalidomide or a rat polyclonal anti-TNFalpha antibody attenuated carrageenan-induced hyperalgesia and prevented priming. Intrathecal administration of antisense to tumour necrosis factor receptor type-1 (TNFR1) reduced the level of TNFR1 transported toward the peripheral terminals of sensory neurons, and attenuated both carrageenan- and rrTNFalpha-induced priming. Acute hyperalgesia induced by carrageenan or rrTNFalpha remained intact in animals treated with TNFR1 antisense. Our results demonstrate that the generation of the primed state does not require production of hyperalgesia and that TNFalpha, which is generated during acute inflammation, can act on sensory neurons to induce hyperalgesic priming by activating neuronal PKC epsilon.
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PMID:Tumor necrosis factor receptor type-1 in sensory neurons contributes to induction of chronic enhancement of inflammatory hyperalgesia in rat. 1275 84

1. FK506 and cyclosporin A (CsA) are immunosuppressive drugs, that specifically inhibit T-cell activation via calcineurin inhibition. This study was undertaken to investigate whether calcineurin inhibitors exert analgesic actions in rat adjuvant-induced arthritis (AIA), an animal model of rheumatoid arthritis (RA). 2. AIA was induced in female Lewis rats. Single doses of FK506 and CsA were orally administered to arthritic rats 17 days after arthritis induction. Intensity of hyperalgesia was assessed by measuring the pain threshold of hind paws. Tumor necrosis factor (TNF)-alpha, IL-1beta and PGE(2) levels in paw extracts were determined by ELISA. TNF activity was measured by L929 cell cytotoxicity assay. IL-1beta and cyclooxygenase (COX) mRNA expression in arthritic paws were measured by RT-PCR. 3. Single doses of FK506 and CsA markedly reduced joint hyperalgesia 24 h after drug administration, without affecting inflammation in an advanced stage of AIA. 4. The calcineurin inhibitors partially reduced the elevated level of TNF-alpha in arthritic paws, however, the analgesic effects of these drugs were not associated with the reduction in TNF-alpha level. 5. Moreover, treatment with anti-rat TNF-alpha antibody did not affect the hyperalgesia, when TNF-alpha activity was suppressed in arthritic paws by that treatment. 6. Both calcineurin inhibitors reduced the elevated level of IL-1beta in arthritic paws to a normal level, 24 h after drug administration. 7. FK506 reduced IL-1beta and COX-2 mRNA expression and PGE(2) level in arthritic paws. 8 In conclusion, calcineurin inhibitors rapidly reduce joint hyperalgesia probably by downregulating IL-1beta, but not TNF-alpha, in AIA. Our findings may provide a new strategy for the treatment of pain in RA.
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PMID:Calcineurin inhibitors exert rapid reduction of inflammatory pain in rat adjuvant-induced arthritis. 1283 66

In cancer therapy outgrowth of chemoresistant tumor cells is the most important factor that ultimately determines-apart from immediate adverse effects during treatment-the life span and prognosis of cancer patients. Despite many advances in cancer treatment and the integration of supportive medications, including new and better drugs for pain management, antiemesis, infection, and reconstitution of the hematopoietic system, both toxic effects and the development of resistance in response to the treatment remain a major problem. New treatment regimens have to be developed to target cancer more specifically using multiple cellular pathways. This will reduce toxic effects as well as the development of chemoresistance. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is the ligand for death receptors that belong to the TNF death receptor family. TRAIL triggers apoptosis in vitro in various cancer cell types. The antitumor drug, Paclitaxel (PA) was shown to increase the survival of patients with cancer. In in vitro experiments, PA also induces apoptosis in cancer cells. Together, PA and TRAIL lead to tumor regression in in vivo therapy and induce apoptosis through the interaction of TNF family death receptors, caspase activation, and?or cytochrome c release from mitochondria. PA and TRAIL complement each other using two distinct pathways that trigger apoptosis in addition to the anti-microtubule effect of PA. The combination of TRAIL and PA suppresses tumor growth that is otherwise resistant to treatment with either PA or TRAIL alone, by improving proapoptotic effects of the drugs. This observation support the use of the PA and TRAIL in future clinical trials.
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PMID:Additive effects of TRAIL and paclitaxel on cancer cells: implications for advances in cancer therapy. 1511 Jan 87

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant inherited condition of periodic fever and pain. Most patients are of northern European descent. The attacks manifest as fever and pain in the joints, abdomen, muscles, skin, or eyes, with variations across patients. An acute-phase response occurs during the attacks. Patients with TRAPS are at risk for AA amyloidosis, the most common targets being the kidneys and liver. Soluble TNFRSF1A is usually low between the attacks and may be normal during the attacks, when TNF levels are high. TNFRSF1A is found in abnormally high numbers on leukocyte cell membranes. TRAPS is the first condition for which naturally occurring mutations in a TNF receptor were found; the mutations affect the soluble TNFRSF1A gene in the 12p13 region. In some patients, the pathogenesis involves defective TNFRSF1A shedding from cell membranes in response to a given stimulus. Thus, TRAPS is a model for a novel pathogenic concept characterized by failure to shed a cytokine receptor. This review compares TRAPS to other inherited periodic febrile conditions, namely, familial Mediterranean fever, Muckle-Wells syndrome, cold urticaria, and hyper-IgD syndrome. The place of TRAPS relative to other intermittent systemic joint diseases is discussed. Colchicine neither relieves nor prevents the attacks, whereas oral glucocorticoid therapy is effective when used in dosages greater than 20 mg/day. The pathogenic hypothesis involving defective TNFRSF1A shedding suggests that medications targeting TNF may be effective in TRAPS.
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PMID:Tumor necrosis factor receptor-associated periodic syndrome (TRAPS): definition, semiology, prognosis, pathogenesis, treatment, and place relative to other periodic joint diseases. 1528 52


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