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)

Tacrolimus (FK506) is an immunosuppressive drug, widely used for organ transplantation and atopic dermatitis. Tacrolimus exerts its immunosuppressive effects primarily by interfering with the activation of T cells, via inhibition of calcineurin. Recent clinical studies have also demonstrated the efficacy of tacrolimus in the treatment of rheumatoid arthritis (RA), an autoimmune disease in which T cells play a pivotal role in pathogenesis. Inflammatory cytokines such as TNF-alpha, IL-1 beta, and IL-6 are involved in development of the disease. Recently, modes of action of tacrolimus on RA have been intensively studied in in vitro and animal arthritis models, demonstrating that tacrolimus exerts various novel actions as an anti-rheumatic drug. The pharmacological action of tacrolimus suggests that it has potential to specifically suppress the production of pathogenic inflammatory cytokines with a low frequency of infection, improve joint inflammation and bone/cartilage destruction, fully recover loss of functional status, exert rapid relief in arthritic pain, and promote osteogenic and chondrogenic differentiation. Here we review the action of tacrolimus on experimental models of RA, with a focus on our recent studies, and provide further insight into experimental models used for identifying efficacious anti-rheumatic drugs.
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PMID:A review of the action of tacrolimus (FK506) on experimental models of rheumatoid arthritis. 1572 98

Aspirin (ASA) is a widely used oral analgesic which acts as an inhibitor of cyclooxygenase. Acetaminophen (ACET) is also an effective analgesic and may selectively inhibit brain prostaglandin synthetase. Various proinflammatory cytokines injected into the central nervous system show pain behavior. In the present study, the effects of orally administered ASA and ACET on pain behaviors induced by various proinflammatory cytokines were examined. At a dose of 100 mg/kg, ASA or ACET did not affect the pain behavior induced by TNF-alpha (100 pg), IL-1beta (100 pg) or IFN-gamma (100 pg) administered intrathecally. However, at doses of 200 and 300 mg/kg, ASA or ACET significantly and dose-dependently attenuated pain behavior induced by TNF-alpha, IL-1beta or IFN-gamma administered intrathecally. Our results suggest that orally administered ASA and ACET produce antinociception by inhibiting the nociceptive action of TNF-alpha, IL-1beta or IFN-gamma administered intrathecally.
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PMID:Effect of aspirin and acetaminophen on proinflammatory cytokine-induced pain behavior in mice. 1577 6

The antinociceptive effect of nicotine administered intracereboventricularly (i.c.v.) or intrathecally (i.t) in several pain models was examined in the present study. We found that i.t. treatment with nicotine (from 5 to 20 g) dose-dependently blocked pain behavior revealed during the second phase, but not during the first phase in the formalin test. In addition, i.c.v. treatment with nicotine (from 0.1 to 10 microg) dose-dependently attenuated pain behavior revealed during both the first and second phases. In addition to the formalin test, nicotine administered i.c.v. or i.t. attenuated acetic acid-induced writhing response. Furthermore, i.c.v. or i.t. administration of nicotine did not cause licking, scratching and biting responses induced by substance P, glutamate, TNF-alpha (100 pg), IL-1beta (100 pg) and INF-gamma (100 pg) injectied i.t. The antinociception induced by supraspinally-administered nicotine appears to be more effective than that resulting from spinally administered nicotine. Our results suggest that nicotine administration induces antinociception by acting on the central nervous system and has differing antinociceptive profiles according to the various pain models.
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PMID:Antinociceptive effect of nicotine in various pain models in the mouse. 1578 53

Because the etiology of inflammatory bowel diseases is unclear, no causative therapy is available. However, pathophysiology of the disease offers a lot of possibilities to disrupt the inflammatory cascade that maintains the inflammatory process. The aim of every therapy is to maintain remission as long as possible and to amend the natural course of the disease. Pharmacotherapy includes 5-Aminosalicylates, glucocorticoids, immunosupressants (methotrexate, azathioprine) as well as specific pharmacologic interventions like monoclonal antibodies directed against TNF-alpha (Infliximab). Important supportive tools are available to improve symptoms like diarrhea and pain. Dietetic treatment and surgical procedures represent important alternatives or supplement pharmacotherapeutic interventions.
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PMID:[Pharmacologic therapy for inflammatory bowel diseases: hopes, disappointments]. 1580 13

Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autosomal dominant inherited condition of periodic fever and pain. TRAPS is caused by mutations of the TNFRSF1A gene localized at 12p13. The gene encodes extracellular region of the p55 TNF-alpha receptor, resulting in impaired cleavage and down-regulation of the membrane expressed form of the receptor, a diminished shedding of potentially antagonistic soluble form of the receptor and, as a consequence, an unbalanced TNF-alpha action. Most affected patients are from northern Europe. Fever, sterile peritonitis, pleural pain, arthralgia, myalgia, skin rash, and/or conjunctivitis occur during the syndrome episodes; some patients also develop systemic amyloidosis, with some differences among patients. An acute-phase response occurs during the episodes. We describe a case of a 23-year-old Moldavian woman, living in Italy presenting recurrent fever episodes with abdominal pain and skin rash. A biopsy showed small vessel vasculitis. The genetic analysis showed a TNFRSF1A gene (R92Q) mutation. In this paper we report also a literature review on this rare disease.
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PMID:[TRAPS syndrome, a rare cause of fever of unknown origin: case report and review of the literature]. 1585 96

The present study was designed to characterize the possible roles of spinally located cholera toxin (CTX)- and pertussis toxin (PTX)-sensitive G-proteins in pro-inflammatory cytokine induced pain behaviors. Intrathecal injection of tumor necrosis factor-alpha (TNF-alpha; 100 pg), interleukin-1beta (IL-1beta; 100 pg) and interferon-gamma (INF-gamma; 100 pg) showed pain behavior. Intrathecal pretreatment with CTX (0.05, 0.1 and 0.5 mg) attenuated pain behavior induced by TNF-alpha and INF-gamma administered intrathecally. But intrathecal pretreatment with CTX (0.05, 0.1 and 0.5 microg) did not attenuate pain behavior induced by IL-1beta. On the other hand, intrathecal pretreatment with PTX further increased the pain behavior induced by TNF-alpha and IL-1beta administered intrathecally, especially at the dose of 0.5 microg. But intrathecal pretreatment with PTX did not affect pain behavior induced by INF-gamma. Our results suggest that, at the spinal cord level, CTX- and PTX-sensitive G-proteins appear to play important roles in modulating pain behavior induced by pro-inflammatory cytokines administered spinally. Furthermore, TNF-alpha, IL-1beta and INF-gamma administered spinally appear to produce pain behavior by different mechanisms.
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PMID:Differential modulatory effects of cholera toxin and pertussis toxin on pain behavior induced by TNF-alpha, interleukin-1beta and interferon-gamma injected intrathecally. 1597 46

Hill races usually include large downhill running sections, which can induce significant degrees of muscle damage in a field setting. This study examined the link between muscle damage, oxidative stress, and immune perturbations following a 7-km mountainous hill race with 457 m of ascent and 457 m of descent. Venous blood samples were taken from 7 club level runners before, immediately after, and 48 hrs postrace. Samples were analysed for total and differential leukocyte counts, markers of muscle damage (CK), lipid peroxidation (MDA), and acute phase proteins (CRP; fibrinogen; alpha-1-ACT). The total antioxidant status (TEAC) and plasma levels of the proinflammatory cytokines IL-6, IL-8, and TNF-alpha were also determined. Subjective pain reports, and plasma activities of CK, MDA, and circulatory monocytes reached peak values at 48 hrs postrace (p < 0.05). TEAC and the cytokine IL-8 increased immediately after the race (p < 0.05). Plasma TNF-alpha remained unchanged (p > 0.05). Despite the reports of muscle damage and soreness, no evidence of an acute phase response was observed (p > 0.05), which may be explained by the failure of the race to induce a plasma TNF-alpha response. Future studies should examine the link between muscle damage, oxidative stress, and the acute phase response following hill races of longer duration with larger eccentric components.
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PMID:Immune alterations, lipid peroxidation, and muscle damage following a hill race. 1598 88

Adenosine (ADO) is an endogenous purine nucleoside that functions as an extracellular signalling molecule. It is released locally at sites of cellular trauma, and acts on specific cell-surface purinergic receptors (termed P1 receptors) near its site of release to exert its effects. Four subtypes of the P1 family of G-protein-coupled receptors have been identified and cloned: A1, A2A, A2B and A3. A considerable body of evidence, including experimental animal data and preliminary clinical reports, indicates that ADO is involved in modulating endogenous antinociceptive processes in the brain and spinal cord. ADO analogues provide analgesic activity after systemic or spinal administration in a broad spectrum of animal pain models. In addition, iv. ADO infusion has shown benefit in human pain states. The spinal cord is a key site for ADO-mediated modulation of nociception. ADO is well known to act as an inhibitory neuromodulator in the central and peripheral nervous system, and it may act to control N-methyl-D-aspartate (NMDA)- and substance P-mediated events in nociception and central sensitisation at the spinal level. ADO is also released at sites of inflammation and it exerts anti-inflammatory effects via multiple mechanisms involving several cell types. These include effects on neutrophil function, endothelial cell permeability, in vivo and in vitro release of tumour necrosis factor (TNF-alpha and collagenase expression in synoviocytes. Accordingly, ADO analogues are effective in several animal models of inflammation, including the rat adjuvant arthritis model. Several therapeutic approaches to pain and inflammation, based on mimicking or modulating the effects of endogenous ADO, are currently under preclinical and clinical investigation. These include the use of ADO itself, the use of direct-acting ADO receptor agonists and the use of agents designed to modulate the levels and, therefore, the actions of ADO in the extracellular space (ADO kinase (AK) inhibitors). Data emerging in the next several years should indicate whether these strategies represent a therapeutically useful new approach to analgesia and inflammation.
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PMID:Adenosine modulation: a novel approach to analgesia and inflammation. 1599 91

Distal sensory polyneuropathy (DSP) is currently the most common neurological complication of HIV infection in the developed world and is characterized by sensory neuronal injury accompanied by inflammation, which is clinically manifested as disabling pain and gait instability. We previously showed that feline immunodeficiency virus (FIV) infection of cats caused DSP together with immunosuppression in cats, similar to that observed in HIV-infected humans. In this study, we investigated the pathogenic mechanisms underlying the development of FIV-induced DSP using feline dorsal root ganglia (DRG) cultures, consisting of neurons, Schwann cells, and macrophages. FIV-infected cultures exhibited viral Ags (p24 and envelope) in macrophages accompanied by neuronal injury, indicated by neurite retraction, neuronal loss and decreased soma size, compared with mock-infected (control) cultures. FIV infection up-regulated inducible NO synthase (iNOS), STAT-1, and TNF-alpha mRNA levels in DRG cultures. Increased STAT-1 and iNOS mRNA levels were also observed in DRGs from FIV-infected animals relative to mock-infected controls. Similarly, immunolabeling studies of DRGs from FIV-infected animals showed that macrophages were the principal sources of STAT-1 and iNOS protein production. The iNOS inhibitor aminoguanidine reduced nitrotyrosine and protein carbonyl levels, together with preventing neuronal injury in FIV-infected DRG cultures. The present studies indicate that FIV infection of DRGs directly contributes to axonal and neuronal injury through a mechanism involving macrophage immune activation, which is mediated by STAT-1 and iNOS activation.
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PMID:Lentivirus infection causes neuroinflammation and neuronal injury in dorsal root ganglia: pathogenic effects of STAT-1 and inducible nitric oxide synthase. 1600 13

Interleukin-12 (IL-12) is an inflammatory Th1-driving cytokine that has been clinically used as immune therapy and vaccine adjuvant. Recently, it was reported that patients receiving IL-12 presented hyperalgesia. In the present study, we investigated the mechanical hyperalgesic effect of IL-12 in rats using two tests: 1) paw constant pressure and 2) electronic pressure-meter. In both tests, intraplantar administration of IL-12 (3-30 ng paw(-1)) caused a dose- and time-dependent mechanical hyperalgesia, which peaked between 3 to 5 h, remaining significantly different from control levels until 7 h and resolved 24 h postinjection. However, the same doses of IL-12 did not induce thermal hyperalgesia, determined using the Hargreaves test. Pretreatments with effective doses of indomethacin (2.5 mg kg(-1)), atenolol (1 mg kg(-1)), 3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-t-butylthioindol-2-yl]-2,2-dimethylpropanoic acid, sodium (MK886) (5-lipoxygenase activating protein inhibitor; 1 mg kg(-1)), or cyclo[(D)Trp-(D)Asp-Pro-(D)Val-Leu] (BQ123) [endothelin (ET)(A) receptor antagonist; 30 nmol paw(-1)] did not inhibit IL-12-evoked mechanical hyperalgesia (10 ng paw(-1)). However, dexamethasone (2 mg kg(-1)), morphine (3-12 microg paw(-1)), and N-cys-2,6 dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D-1-methoxycarboyl-d-norleucine (BQ788) (ET(B) receptor antagonist; 3-30 nmol paw(-1)) did inhibit IL-12 hyperalgesia. Furthermore, neither pretreatment with effective doses of antiserum against rat-TNF-alpha (50 microl paw(-1)) nor against IL-18 (10 microg paw(-1)) inhibited the IL-12-induced hyperalgesia. Likewise, antiserum against IL-12 (10 ng paw(-1)) did not alter IL-18-induced hyperalgesia. In conclusion, we demonstrated for the first time that IL-12 is a prohyperalgesic cytokine that induces mechanical hyperalgesia mediated by endothelin action on the ET(B) receptor. Therefore, endothelin receptor antagonism could be beneficial in controlling IL-12 therapy-induced pain or hyperalgesia.
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PMID:Nociceptive effect of subcutaneously injected interleukin-12 is mediated by endothelin (ET) acting on ETB receptors in rats. 1602 32


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