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)

As a mediator of neurogenic inflammation and pain, we hypothesized that levels of the neuropeptide Substance P (SP) would be elevated in patients with sickle cell disease (SCD) with vaso-occlusive pain crisis. SP is a known stimulator of tumor necrosis factor-alpha (TNF-alpha) release and a promoter of interleukin-8 (IL-8), which are reported to be increased in SCD. These cytokines enhance adhesion of leukocytes to endothelium and may play a role in vaso-occlusive events. Serum levels of IL-8, TNFalpha, and SP were studied in three groups of children aged 2 to 18 years: 30 well children with SCD, 21 with SCD in pain crisis, and 20 healthy age-matched controls. Serum levels of SP were elevated in all SCD patients and were highest in patients in pain crisis. The percentage of sera with detectable levels of IL-8 (>5.0 pmol/L) was increased in SCD patients as compared with the control group. IL-8 levels were similar for well SCD patients and those with pain. TNFalpha levels were not significantly different among the three groups. In three children with SCD, SP was measured at baseline and again during pain crisis. In each case, serum levels during pain crisis were higher than they were when the patient was well. We conclude that levels of SP are high in patients with SCD and increase during pain crisis. These results imply that SP plays a prominent role in the pain and inflammation of SCD and may be a measurable laboratory marker of vaso-occlusive crisis. We speculate that neurokinin receptor antagonists may have a therapeutic potential in the treatment of crisis pain.
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PMID:Serum levels of substance P are elevated in patients with sickle cell disease and increase further during vaso-occlusive crisis. 978 50

Rheumatoid arthritis is a chronic inflammatory disease that can cause severe pain and disability. Disease management historically was based on a "therapeutic pyramid" in which treatment escalated as symptoms worsened. However, the demonstration of early joint damage in patients with rheumatoid arthritis has emphasized the importance of early identification and treatment. Key features in establishing a diagnosis include joint examinations, assessments of extra-articular manifestations, laboratory tests, and radiologic examinations. Care must be taken to rule out other disorders with symptoms that overlap those of rheumatoid arthritis. Treatment of rheumatoid arthritis typically involves disease-modifying antirheumatic drugs, nonsteroidal anti-inflammatory drugs, and low-dose corticosteroids--often used in combination. A new class of therapeutic agents designed to neutralize inflammatory cytokines has added a new dimension to the therapeutic armamentarium against rheumatoid arthritis. Etanercept, a bioengineered soluble receptor fusion protein that blocks tumor necrosis factor activity, is the first compound in this class to be approved for treatment of patients with refractory rheumatoid arthritis. Therapeutic trials indicate that etanercept can reduce disease activity with relatively few drug-related adverse effects, thus helping persons with rheumatoid arthritis return to more normal, healthy lives.
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PMID:Rheumatoid arthritis and primary care: the case for early diagnosis and treatment. 1040 18

We investigated whether interleukin-1 (IL-1), a mediator of inflammatory pain, also plays a role in pain induced by nerve injury. Female C57BL/6-mice with a chronic constrictive injury of one sciatic nerve, an established model of neurogenic hyperalgesia and allodynia, were treated with different doses (10-80 microg) of a neutralizing monoclonal rat antibody to IL-1 receptor I (anti-IL-1RI). This antibody dose-dependently reduced thermal hyperalgesia and mechanical allodynia in the animals. Furthermore, immunoreactivity for the proinflammatory cytokine tumor necrosis factor-alpha (TNF) was reduced in mice treated with the highest dose of anti-IL-1RI. Degeneration of myelinated fibers was not altered by any of the treatment schedules. We conclude that IL-1 may be a mediator of hyperalgesia after nerve lesion.
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PMID:Neutralizing antibodies to interleukin 1-receptor reduce pain associated behavior in mice with experimental neuropathy. 1045 37

Wallerian degeneration, induced after injury to a peripheral nerve, is associated with upregulation of proinflammatory cytokines, which are suggested to contribute to the development of lesion-induced neuropathic pain. In chronic constrictive injury (CCI), an animal model of injury-induced painful mononeuropathy, inhibition of synthesis, release, or function of the cytokine tumor necrosis factor-alpha (TNF) results in reduced pain-associated behavior. Here, changes of TNF content in rat sciatic nerves after CCI (days 0, 0.5, 1, 3, 7 and 14) were investigated by enzyme-linked-immunoassay. Low levels of TNF were already detectable in control nerves. Concentrations increased rapidly after CCI, with a maximum (2.7-fold) at 12 h, and remained elevated on a lower level until day 3. Baseline levels were reached again at day 14. These results indicate that TNF is produced at an early time point in the cascade of events resulting in Wallerian degeneration and hyperalgesia following peripheral nerve injury. Given that only prophylactic treatment with TNF inhibitors efficiently reduces hyperalgesia in CCI, TNF seems to contribute to the initiation of neuropathic pain in this model.
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PMID:Serial determination of tumor necrosis factor-alpha content in rat sciatic nerve after chronic constriction injury. 1063 Jan 97

The pleiotropic cytokine tumor necrosis factor-alpha (TNFalpha) is implicated in the development of persistent pain through its actions in the periphery and in the central nervous system (CNS). Activation of the alpha(2)-adrenergic receptor is associated with modulation of pain, possibly through its autoregulatory effect on norepinephrine (NE) release in the CNS. The present study employs a chronic constriction nerve injury (CCI) pain model to demonstrate the interactive role of presynaptic sensitivity to TNFalpha and the alpha(2)-adrenergic autoreceptor in the pathogenesis of neuropathic pain. Accumulation of TNFalpha is increased initially in a region of the brain containing the locus coeruleus (LC) at day 4 post-ligature placement, followed by an increase in TNFalpha in the hippocampus at day 8 post-ligature placement, coincident with hyperalgesia. Levels of TNFalpha in the thoraco-lumbar spinal cord are also increased at day 8 post-ligature placement. Concurrently, alpha(2)-adrenergic receptor and TNFalpha-induced inhibition of NE release are increased, and stimulated NE release is decreased in superfused hippocampal slices isolated at day 8 post-ligature placement. Stimulated NE release is also decreased in spinal cord slices (lumbar region) from animals undergoing CCI, although in contrast to that which occurs in the hippocampus, alpha(2)-adrenergic receptor inhibition of NE release is not changed. These results indicate an important role that TNFalpha plays in adrenergic neuroplastic changes in a region of the brain that, among its many functions, appears to be a crucial link in the conscious perception of pain. We predict that neuroplastic changes, involving increased functional responses of alpha(2)-adrenergic autoreceptors and increased presynaptic sensitivity to TNFalpha, culminate in decreased NE release in the CNS. These neuroplastic changes provide a mechanism for the role of CNS-derived TNFalpha in the pathogenesis of persistent pain.
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PMID:Brain-derived TNFalpha: involvement in neuroplastic changes implicated in the conscious perception of persistent pain. 1072 Jun 20

The perception of pain sensation (threshold), whether local or central, is altered by inflammatory processes. Anti-inflammatory drugs block this by raising the pain threshold and by reducing the inflammatory process. Melatonin is claimed to have anti-inflammatory activity in animal models of acute and chronic inflammation. However, it is not known whether melatonin can reverse the hyperalgesia that is secondary to the inflammation. The present study aimed to assess the modulatory effect of melatonin on lipopolysaccharides-induced alteration of pain perception in mice. Central perception of pain was assessed with the tail-flick and hot-plate methods and local hyperalgesia was assessed by noting the animal's reactions such as paw licking and rearing after the intraplantar injection of lipopolysaccharides (5 microg/paw). Local administration (intraplantar) of lipopolysacharides induced hyperalgesia when measured by both central effects and behavioral reactions. Melatonin (5 and 10 mg/kg), like dexamethasone (0.5 mg/kg), given 30 min prior to, and 4 and 8 h after lipopolysaccharides (5 microg/paw) challenge attenuated central and behavioural hyperalgesia. The attenuation of lipopolysaccharides-induced hyperalgesia by melatonin was not reversed by naltrexone (4 mg/kg). In vitro studies showed that melatonin, in concentrations ranging from 100 to 1000 nM, suppressed tumor necrosis factor-alpha (TNF-alpha) without affecting the nitric oxide (NO) release in lipopolysaccharides-activated murine peritoneal macrophages. Taken together, the present results demonstrated that melatonin reverses lipopolysaccharides-induced hyperalgesia.
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PMID:Melatonin reversal of lipopolysacharides-induced thermal and behavioral hyperalgesia in mice. 1078 68

Recently, we have developed a model of delayed (12 h) increase in sensitivity (allodynia) to rectal distension (RD) induced by intraperitoneal lipopolysaccharide (LPS) in awake rats. Thus, we examined whether central interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) are involved in LPS response. Abdominal contractions (criterion of visceral pain) were recorded in rats equipped with intramuscular electrodes. RDs were performed at various times after pharmacological treatments. RD induced abdominal contractions from a threshold volume of distension of 0.8 ml. At lowest volume (0.4 ml), this number was significantly increased 12 h after LPS. Intracerebroventricular (i.c.v.) injection of IL-1 receptor antagonist, IL-1beta converting enzyme inhibitor or recombinant human TNF-alpha soluble receptor reduced LPS-induced increase of abdominal contractions at 0.4 ml volume of distension. When injected i.c.v., recombinant human IL-1beta and recombinant bovine TNF-alpha reproduced LPS response at 9 and 12 h and at 6 and 9 h, respectively. These data suggest that IL-1beta and TNF-alpha act centrally to induce delayed rectal hypersensitivity and that central release of these cytokines is responsible of LPS-induced delayed (12 h) rectal allodynia.
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PMID:Brain interleukin-1beta and tumor necrosis factor-alpha are involved in lipopolysaccharide-induced delayed rectal allodynia in awake rats. 1082 65

Inhibition of proinflammatory cytokines reduces hyperalgesia in animal models of painful neuropathy. We set out to investigate the consequences of this treatment for nerve regeneration. Here we examined the sequels of epineurial application of neutralizing antibodies to tumor necrosis factor-alpha (TNF) in chronic constriction injury (CCI) of the sciatic nerve in C57/BL 6 mice. The mice were tested behaviorally for manifestations of thermal hyperalgesia and mechanical allodynia. Nerve regeneration was assessed by morphometry of myelinated nerve fibers in the sciatic nerve and of the epidermal innervation density in the glabrous skin of the hindpaws. Antibodies to TNF reduced thermal hyperalgesia and mechanical allodynia after CCI. Myelinated fiber density in the sciatic nerve was reduced to 30% of normal on day 7 after surgery, and reached 60% on day 45, with no difference between antibody-treated and untreated animals. Epidermal innervation density as shown by PGP 9.5 and CGRP immunohistochemistry was reduced to 25-47% at both time points after CCI, again without differences between antibody treated and untreated mice. Myelinated fiber density but not epidermal innervation density was correlated to thermal and mechanical withdrawal thresholds. We conclude that neutralization of endoneurial TNF attenuates pain related behavior but has no effect on nerve regeneration. Furthermore, the number of epidermal nerve fibers is not relevant to the magnitude of behavioral hyperalgesia in CCI.
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PMID:Effects of neutralizing antibodies to TNF-alpha on pain-related behavior and nerve regeneration in mice with chronic constriction injury. 1082 76

Several independent pathophysiological mechanisms in both the peripheral and central nervous system are responsible for sensory symptoms as well as spontaneous and evoked pains in peripheral neuropathies: (1) Pathologic active or sensitized nociceptors can induce secondary changes in central processing, leading to spinal cord hyperexcitability that causes input from mechanoreceptive Abeta-fibers (light touching) to be perceived as pain. These patients characteristically have spontaneous pain, heat hyperalgesia, static mechanical allodynia, and and severe dynamic mechanical allodynia. (2) Nociceptor function may be selectively impaired within the allodynic skin. Pain and temperature sensation are profoundly impaired but light moving mechanical stimuli can often produce severe pain (dynamic mechanical allodynia). Anatomic reorganization in the dorsal horn resulting from C-fiber degeneration may lead to Abeta-fiber-mediated allodynia. (3) Persistent inflammatory reactions of the nerve trunk can induce ectopic activity in primary afferent nociceptors and thus is a potential cause of spontaneous pain and allodynia. This effect is mediated by the cytokine tumor necrosis factor-alpha produced by activated macrophages. (4) After nerve lesion the sympathetic nervous system might interact with afferent neurons. Activity in sympathetic fibers can induce further activity in sensitized nociceptors and, therefore, enhance pain and allodynia (sympathetically maintained pain). This pathologic interaction acts via noradrenaline released from sympathetic terminals and newly expressed receptors on the afferent neuron membrane. These mechanisms can operate in concert in a single disease entity (e.g., postherpetic neuralgia) and also in a single patient. Distinct pathophysiological mechanisms lead to specific sensory symptoms (e.g., dynamic mechanical allodynia, cold hyperalgesia). It is also possible that the pain-generating mechanism and the symptoms change during the course of the disease. A thorough analysis of sensory symptoms may, reveal the underlying mechanisms that are mainly active in a particular patient. The treatment of neuropathic pain is currently unsatisfactory. In the future, drugs will be developed that address specifically the relevant combination of mechanisms.
Clin J Pain 2000 Jun
PMID:Peripheral neuropathic pain: from mechanisms to symptoms. 1087 Jul 35

With the success of high dose therapy supported by autologous bone marrow transplantation (ABMT) for malignant lymphomas, medical late-effects and secondary effects on subjective health, like fatigue, are of concern. Fatigue is poorly understood and correlates have been barely addressed. Health-related quality of life (HRQL), fatigue, and correlates to fatigue, including endocrinological status and serum levels of interleukin-6, tumor necrosis factor, and soluble tumor necrosis factor receptors, were investigated in a cross-sectional study of 33 lymphoma patients (median age 39 years) 4-10 years after ABMT. The survivors were compared to general population norms. Fatigue was highly prevalent, and females reported significantly more fatigue and impaired HRQL compared to males and the normal population. Gonadal dysfunction was found in the majority of the patients, but no statistically significant endocrinological or immunological associations with fatigue could be demonstrated. The high level of fatigue among female long-term survivors after ABMT may be related to the gonadal dysfunction, but further studies of possible mechanisms behind fatigue are necessary.
J Pain Symptom Manage 2000 Jun
PMID:High level of fatigue in lymphoma patients treated with high dose therapy. 1090 25


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