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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The inflammatory component of peripheral nerve injury may affect the development of local neuropathologic changes as well as the onset of hyperalgesia, the characteristic features of experimental neuropathic pain states. The goal of this study was to determine whether local sciatic injection of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha could reproduce the nociceptive behaviors and endoneurial pathology found following experimental nerve injuries. TNF injection caused significant thermal hyperalgesia and mechanical allodynia for 3 days post-injection in association with nerve edema, splitting of myelin lamellae with vacuolization, Schwann cell injury, fibroblast and macrophage activation, and phagocytosis of lipid debris. The data show that subperineurial injection of TNF proximal to peripheral sensory receptors generates the transient display of behaviors and endoneurial pathologies found in experimental painful nerve injury, and implicates local TNF in the pathologies of neuropathic pain.
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PMID:Endoneurial injection of TNF-alpha produces neuropathic pain behaviors. 911 5

The physiological and behavioral disturbances observed during an infection can be reproduced by systemic administration of proinflammatory cytokines (e.g., interleukin (IL)-1, IL-6, tumor necrosis factor-alpha) or lipopolysaccharide (LPS), a potent inducer of these cytokines. It is now well established that these molecules induce their effects by acting centrally, however, the mechanisms by which they reach central structures are not clear. We have earlier proposed that the humoral immune message is converted to a central neural activation by the action of cytokines on peripheral terminations of afferent neurons. Subdiaphragmatic vagotomy abolishes several effects of peripherally injected IL-1beta and LPS (e.g., decreased food-motivated behavior and social exploration, central expression of cytokines). To further define the nature of the peripheral fibers implicated in this phenomenon, we used a potent sensory neurotoxin, capsaicin, to selectively destroy C-fiber afferents. Adult rats were injected I.P. with a total dose of 25 mg/kg capsaicin in a series of 10 injections over a 48-h period. Adult mice were injected I.P. with a total dose of 75 mg/kg in a series of seven injections over a 7-day period. Although capsaicin treatment altered visceral chemosensory function, corneal and pain sensitivity, vagal-mediated anorexic effects of cholecystokinin, and depleted levels of substance P in the thoracic spinal cord, it was completely ineffective in blocking the decrease in food-motivated behavior induced by IL-1beta (4 microg/rat I.P. in rats) and LPS (250 microg/kg I.P. in rats and 400 microg/kg I.P. in mice). Thus, other afferents besides capsaicin-sensitive C-fibers appear to be involved in the transduction of cytokine effects during inflammatory and infectious events.
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PMID:Systemic capsaicin pretreatment fails to block the decrease in food-motivated behavior induced by lipopolysaccharide and interleukin-1beta. 912 19

Rheumatoid arthritis (RA) is a chronic multisystemic inflammatory disease with autoimmune features, and of unknown cause, associated with characteristic joint deformities and increased mortality rate. The pathogenesis of this serious disease seems to be multifactorial, where several cytokines, particularly interleukin-1 and tumor necrosis factor-alpha, are strongly involved in the induction and perpetuation of the chronic inflammatory process of the joints in RA and in the systemic manifestations of the disease. Other factors, such as reactive oxygen species and metalloproteinases, may also participate in the destruction of the rheumatoid joint. Current treatments of RA are inadequate in that they only partially control established RA, and despite optimal use of current antirheumatic agents, the outcome of many patients with RA consists of pain, severe functional decline, and premature death. The gloomy recent data regarding the prognosis of RA with the use of the current treatments stress the need for new therapeutic regimens with the ability to effectively control the inflammatory process in the rheumatoid joint and to induce long-term remission or even cure. Controlling the production and the activity of the factors involved in the pathogenesis of the disease represents the major therapeutic goal. Since several factors are involved in the pathogenesis of RA, neutralizing one or some of these factors may be of only limited benefit. In this regard, interleukin-4 may be a very promising agent for an effective treatment of RA, because this cytokine is not limited by its inhibitory effects to a single factor, but rather it inhibits most of the main factors involved in the pathogenesis of the disease. Although recent data strongly support this approach with interleukin-4, controlled long-term clinical trails should be undertaken in order to prove the validity and the effectiveness of this promising approach.
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PMID:New insights into the pathogenesis and treatment of rheumatoid arthritis. 914 71

Nerve injury leads to central neuroimmunologic responses that may be integral to the development and maintenance of chronic neuropathic pain in humans. Recent data have demonstrated that cytokines and growth factors may be strongly implicated in the generation of pain states at both peripheral and central nervous system sites. We utilized immunohistochemical methods to investigate this phenomenon in rat models of neuropathic pain. Specifically, we employed well-characterized models of neuropathy that result in behaviors suggestive of neuropathic pain in humans; a freeze lesion of the sciatic nerve, termed sciatic cryoneurolysis, and a chronic constriction sciatic nerve injury. We used immunohistochemistry to examine spinal localization of the cytokines, interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and the growth factors, basic fibroblast growth factor (bFGF), and transforming growth factor-beta1 (TGF-beta) at 3, 14, and 35 days following sciatic cryoneurolysis or 6 days following chronic constriction injury as compared with normal, unoperated rats. There was minimal, diffuse cytokine/growth factor staining in lumbar spinal tissue from the normal group. However, cell profile quantification demonstrated increases in lumbar spinal IL-1beta-, TNF-alpha- and TGF-beta-like immunoreactivity (LI) in both mononeuropathy models studied. At 3 days following sciatic cryoneurolysis, intense bFGF LI was present in the ipsilateral dorsal and ventral horn. By 14 days bFGF LI was also observed in contralateral dorsal and ventral horns. In contrast, we found no obvious staining differences in lumbar spinal cord following the chronic constriction injury. This study demonstrated increased specific cytokine and growth factor-like expression in the spinal cord following peripheral nerve injuries. It also showed a differential expression of bFGF in two distinct mononeuropathy models. These results provide further evidence that central cytokine production via a neuroimmune cascade may be involved in the development and maintenance of behaviors that mimic neuropathic pain following nerve injury.
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PMID:Cytokine and growth factor immunohistochemical spinal profiles in two animal models of mononeuropathy. 921 62

Subcutaneous (s.c.) injection of formalin induces a rapid and prolonged hyperalgesia across widespread areas of the body. This hyperalgesic state involves a brain-to-spinal cord pathway, likely arising from the nucleus raphe magnus. The present study examined whether subsequent activation of spinal cord glia may be critical for the hyperalgesic state to be observed in rats. Glia were considered candidates as they can, upon activation, release a variety of substances known to be critical for the mediation of subcutaneous formalin-induced hyperalgesia including glutamate, aspartate, nitric oxide, arachidonic acid and cyclooxygenase products such as prostaglandins. This series of experiments demonstrate that formalin-induced hyperalgesia in rats can be blocked by intrathecal administration of agents that: (a) disrupt glial function (using either 1 nmol fluorocitrate which is a glial metabolic inhibitor, or 9 microg CNI-1493 which disrupts synthesis of nitric oxide and cytokines in monocyte-derived cells; ANOVA revealed reliable group effects for each drug with P < 0.0005); or (b) disrupt the action of glial products (using 10, 50, or 100 microg of a human recombinant interleukin-1 receptor antagonist or 10 microl antibody directed against nerve growth factor; ANOVA revealed reliable group effects for each drug with P < 0.001). Disruption appeared to be selective, as blockade of only select glial products was effective. That is, up to 120 microg of a functional antagonist of tumor necrosis factor-alpha (TNF binding protein) and 5 microl of an antibody against complement-3 produced no statistically reliable reduction in formalin-induced hyperalgesia. Taken together, the present series of experiments suggest an important role for spinal glial cells in the cascade of events that are initiated by descending signals following s.c. administration of formalin.
Pain 1997 Jul
PMID:Evidence for the involvement of spinal cord glia in subcutaneous formalin induced hyperalgesia in the rat. 923 65

In addition to their capacity to induce pain, vasodilatation and fever, prostaglandins E (PGE) exert anti-inflammatory activities by inhibiting the release of pro-inflammatory cytokines by macrophages and T cells, and by increasing interleukin (IL)-10 production by macrophages. We here report that PGE2, the major arachidonic acid metabolite released by antigen-presenting cells (APC), primes naive human T cells for enhanced production of anti-inflammatory cytokines and inhibition of pro-inflammatory cytokines. Unfractionated as well as CD45RO- CD31+ sort-purified neonatal CD4 T cells acquire the capacity to produce a large spectrum of cytokines after priming with anti-CD3 and anti-CD28 monoclonal antibodies (mAb), in the absence of both APC and exogenous cytokines. PGE2 primes naive T cells in a dose-dependent fashion for production of high levels of IL-4, IL-10 and IL-13, and very low levels of IL-2, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and TNF-beta. PGE2 does not significantly increase IL-4 production in priming cultures, whereas it suppresses IL-2 and IFN-gamma. Addition of a neutralizing mAb to IL-4 receptor in primary cultures, supplemented or not with PGE2, prevents the development of IL-4-producing cells but does not abolish the effects of PGE2 on IL-10 and IL-13 as well as T helper (Th)1-associated cytokines. Addition of exogenous IL-2 in primary cultures does not alter the effects of PGE2 on naive T cell maturation. Thus PGE2 does not act by increasing IL-4 production in priming cultures, and its effects are partly IL-4 independent and largely IL-2 independent. Together with the recent demonstration that PGE2 suppresses IL-12 production, our results strongly suggest that this endogenously produced molecule may play a significant role in Th subset development and that its stable analogs may be considered for the treatment of Th1-mediated inflammatory diseases.
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PMID:Prostaglandin E2 primes naive T cells for the production of anti-inflammatory cytokines. 946 43

Wallerian degeneration with macrophage influx and production of proinflammatory cytokines is a critical factor in the development of hyperalgesia in animal models of neuropathic pain. We hypothesized that in the mouse strain with delayed Wallerian degeneration, the C57BL/Wld mouse, the temporal course of mechanical allodynia and thermal hyperalgesia as well as the temporal profile of cytokine expression after nerve injury would differ from normal mice. Here we used the model of chronic constriction injury of the sciatic nerve (CCI) to study the correlation of pain related behavior with peripheral nerve de- and regeneration and concomitant cytokine production. Indeed, after CCI, C57BL/Wld mice showed markedly reduced thermal hyperalgesia compared to normal C57BL/6 mice, temporally related to the delayed recruitment of hematogeneous macrophages to the injured nerve. Endoneurial tumor necrosis factor-alpha (TNF)-like immunoreactivity increased rapidly in normal mice but did so with a delayed time course in C57BL/Wld mice. In addition, the duration of mechanical allodynia was significantly prolonged in C57BL/Wld mice as compared to C57BL/6 mice, in accordance with the delay in regeneration of sensory nerve fibers in these mice. These results suggest that macrophage invasion and production of TNF may influence the development of thermal hyperalgesia and that regenerative activity is linked to mechanical allodynia in peripheral mononeuropathy.
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PMID:Painful mononeuropathy in C57BL/Wld mice with delayed wallerian degeneration: differential effects of cytokine production and nerve regeneration on thermal and mechanical hypersensitivity. 951 88

Therapeutic trials in rheumatoid arthritis (RA), osteoarthritis, seronegative spondyloarthopathies, back pain, systemic lupus erythematosus, and systemic sclerosis are reviewed. For RA, minocycline has been proven effective in some subsets of RA, whereas tumor necrosis factor receptor IgG fusion protein appears quite effective for treating the symptoms of RA in a more resistant group. The latter trial illustrates the importance of tumor necrosis factor in RA. Also, the triple combination of hydroxychloroquine, sulfasalazine, and methotrexate is very effective even in resistant RA. In osteoarthritis, the effects of nonsteroidal anti-inflammatory drugs, intra-articular steroids, and biologics are reviewed, with generally nondifferentiable nonsteroidal anti-inflammatory drug effects and some short-term intra-articular effects of new biologics. Sulfasalazine is moderately effective for ankylosing spondylitis and psoriatic arthritis, although the large placebo response in the latter makes it more difficult to show responses. Trials in the treatment of back pain are beginning to be published, with a large cohort study over 1 year favoring surgery for early relief of pain in both sciatica and lumbar stenosis, but not showing a clear advantage in functional outcome at 1 year. Finally, early reports show the ability of dihydroepiandrosterone to decrease steroid use in systemic lupus erythematosus, whereas Relaxin appears to be effective in decreasing skin involvement in systemic sclerosis. These trials demonstrate in numerous ways the need to consider the elements of good trial design when testing therapeutic modalities in the rheumatic diseases. These key elements include 1) careful patient definition and selection; 2) removal of bias (requiring blinding, randomization, prospective studies, and often, placebo); 3) use of well-defined outcomes; and 4) careful analytic techniques.
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PMID:Update on clinical trials in the rheumatic diseases. 956 7

Recent evidence points to a role of cytokines like tumor necrosis factor-alpha (TNF) in the generation of hyperalgesia not only in inflammatory, but also in neuropathic pain. We used the model of chronic constrictive injury (CCI) of one sciatic nerve in the mouse to investigate which of the two known TNF receptors is involved in the process that leads to hyperalgesia after nerve injury. Neutralizing antibodies to TNF, to the TNF receptor 1 (TNFR1), and to the TNF receptor 2 (TNFR2) were administered by epineurial injection once daily to mice with CCI. Testing of the animals' hind paws with thermal and innocuous mechanical stimuli revealed a reduction in thermal hyperalgesia and mechanical allodynia in mice treated with neutralizing antibodies to TNF and to TNFR1. Neutralizing antibodies to TNFR2 had no effect. We conclude that TNFR1, but not TNFR2, is mediating thermal hyperalgesia and mechanical allodynia after nerve injury.
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PMID:Hyperalgesia in experimental neuropathy is dependent on the TNF receptor 1. 958 61

We investigated the effects of (+)-4-[(alpha R)-alpha-((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N, N-diethylbenzamide (SNC 80), a nonpeptidic delta-opioid receptor-selective agonist, on rat leukocyte functions. Intracerebroventricular injection of SNC 80 (20 nmol) in Fischer 344N male rats did not affect splenic natural killer cell activity compared with intracerebroventricular saline-injected controls. SNC 80 also had no effect on concanavalin A-, anti-T cell receptor-, interleukin-2- and anti-T cell receptor + interleukin-2-induced splenic and thymic lymphocyte proliferation in most experiments. In some experiments, however, SNC 80 significantly (P < .01) caused a 41 to 93% increase of concanavalin A-, anti-T cell receptor-, interleukin-2- and anti-T cell receptor + interleukin-2-induced splenic lymphocyte proliferation compared to controls. Additionally, SNC 80 did not significantly affect splenic T cell or natural killer cell populations as measured by the expression of T cell receptoralphabeta, and T helper (CD4), T suppressor/cytotoxic (CD8) and natural killer cell surface markers. Finally, SNC 80 did not affect interferon-gamma- or lipopolysaccharide (LPS)-induced splenic nitric oxide, and LPS-induced tumor necrosis factor-alpha production by splenic macrophages. These results suggest that SNC 80 could be useful in the treatment of pain without suppressing immune function. However, the potential immunoenhancing properties of SNC 80 may be also valuable in immunocompromised individuals.
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PMID:Rat natural killer cell, T cell and macrophage functions after intracerebroventricular injection of SNC 80. 969 52


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