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)

Nerve injury initiates Wallerian degeneration with subsequent alterations of cytokine expression contributing to neuropathic pain. To investigate the very early temporal pattern of cytokine regulation we studied 140 mice of C57Bl/6J background after chronic constriction injury (CCI) of the right sciatic nerve and measured the relative mRNA expression of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF) and interleukin-1beta (IL-1beta) and of the anti-inflammatory cytokines IL-4 and IL-10 with quantitative real-time polymerase chain reaction (qRT-PCR). The measurements were performed in ipsi- and contralateral sciatic nerves and dorsal root ganglia (DRG) 1, 3, 6, 9, 12, 24 h, and 3 and 7 days after CCI. We found an ipsilateral upregulation of TNF, IL-1beta and IL-10 mRNA levels as early as one hour after CCI. To investigate upstream regulatory mechanisms, we used inhibitors to the N-methyl-d-aspartate (NMDA) receptor ((+)-MK-801) and to calpain (MDL-28170). MDL-28170, but not (+)-MK-801 inhibited TNF and IL-1beta upregulation one hour after CCI. This leads us to suggest that calpain is one of the earliest mediators of cytokine upregulation in injured peripheral nerves.
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PMID:Early cytokine expression in mouse sciatic nerve after chronic constriction nerve injury depends on calpain. 1720 95

Dramatic relief of pain and life-altering changes in quality of life in some patients treated with immunomodulators such as thalidomide compel us to look more closely at unconventional mechanisms that may be involved in propagation of persistent pain. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-10 are the cytokines with the most evidence in pain modulation. TNF-alpha and IL-1beta seem to initiate neuropathic pain, IL-6 maintains such pain, and IL-10 inhibits this persistent pain. Thalidomide was found to be effective in animal models by inhibiting TNF-alpha production. Several case reports and case series in humans have demonstrated mixed results, with some patients having dramatic responses, especially in chronic intractable conditions such as complex regional pain syndrome. Thalidomide may be an alternative for some patients with intractable pain. However, use of thalidomide is limited by its neurotoxic and teratogenic effects. Newer analogues may significantly improve the risk/benefit of using such immunomodulators.
Curr Pain Headache Rep 2007 Apr
PMID:Does thalidomide have an analgesic effect? Current status and future directions. 1736 89

PGs are potent mediators of pain and inflammation. PGE synthases (PGES) catalyze the isomerization of PGH(2) into PGE(2). The microsomal (m)PGES-1 isoform serves as an inducible PGES and is responsible for the production of PGE(2), which mediates acute pain in inflammation and fever. The present study was designed to investigate the regulation of expression of mPGES-1 in polarized phagocytes, which represent central, cellular orchestrators of inflammatory reactions. Here, we report that human peripheral blood monocytes did not express mPGES-1. Exposure to LPS strongly induced mPGES-1 expression. Alternatively activated M2 monocytes-macrophages exposed to IL-4, IL-13, or IL-10 did not express mPGES-1, whereas in these cells, IL-4, IL-13, and to a lesser extent, IL-10 or IFN-gamma inhibited LPS-induced, mPGES-1 expression. It is unexpected that polymorphonuclear leukocytes expressed high basal levels of mPGES-1, which was up-regulated by LPS and down-regulated by IL-4 and IL-13. Induction of mPGES-1 and its modulation by cytokines were confirmed at the protein level and correlated with PGE(2) production. Cyclooxygenase 2 expression tested in the same experimental conditions was modulated in monocytes and granulocytes similarly to mPGES-1. Thus, activated M1, unlike alternatively activated M2, mononuclear phagocytes express mPGES-1, and IL-4, IL-13, and IL-10 tune expression of this key enzyme in prostanoid metabolism. Neutrophils, the first cells to enter sites of inflammation, represent a ready-made, cellular source of mPGES-1.
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PMID:Regulation of the microsomal prostaglandin E synthase-1 in polarized mononuclear phagocytes and its constitutive expression in neutrophils. 1750 22

It has been suggested that dysregulation of immune-to-brain communication plays a role in the biopsychological process underlying medically unexplained symptoms (MUS). Immune and non-immune stressors can both be involved in the activation of the central sickness-behavioural-system leading to complaints like malaise, pain and fatigue. We hypothesized increased pro-inflammatory and/or reduced anti-inflammatory cytokine activity to exist in MUS patients. Twenty-seven participants (4 male; 23 female) with heterogeneous MUS were compared with 27 healthy controls (6 male; 21 females). Blood samples were analysed for leukocyte subset cell counts, in vitro T-cell mitogen-stimulated cytokine production (IL-2, IL-4, IL-5, IL-6, IL-10, TNF-alpha and IFN-gamma) and in vitro monocyte cytokine release (IL-1beta, IL-6, IL-8, IL-10 and TNF-alpha) in response to increasing concentrations of LPS. No significant group differences were found for any of the cytokines measured. One unexpected exception was an elevation in the number of circulating B and NK-cells in participants high on MUS. Nonetheless, no support was found for the hypothesized immunological dysregulation in peripheral blood leukocyte function of MUS patients.
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PMID:Heterogeneous medically unexplained symptoms and immune function. 1755 64

Peripheral arterial disease (PAD) is an atherosclerotic disease. Evidence suggests that atherosclerosis is an inflammatory condition and long chain n-3 fatty acids, found in oily fish and fish oils, have been shown to reduce inflammation. Genetic and lifestyle factors such as body mass index (BMI) also influence inflammation. In this study we have examined the effect of fish oil in patients with claudication secondary to PAD. Fish oil supplementation, providing 1g EPA and 0.7 g DHA per day for 12 weeks, increased walking distance on a treadmill set at 3.2 km/h with a 7% incline. Walking distance to first pain increased from 76.2+/-8.5 m before fish oil to 140.6+/-25.5 m after fish oil (mean+/-SEM, p=0.004) and total distance walked increased from 160.0+/-21.5 m before fish oil to 242.1+/-34.5 m after fish oil (p=0.002). Fish oil supplementation also improved ankle brachial pressure index (ABPI) from 0.599+/-0.017 before fish oil to 0.776+/-0.030 after fish oil (p<0.001). The increase in walking distance was dependent on both BMI and genotype for single nucleotide polymorphisms in the genes encoding the pro-inflammatory cytokines tumour necrosis factor-alpha and interleukin (IL)-1beta and the anti-inflammatory cytokine IL-10 (detected using amplification refractory mutation system polymerase chain reaction). Neither BMI nor any of the genotypes examined affected the ability of fish oil to increase ABPI. The mechanisms by which fish oil affects walking distance and ABPI do not appear to be the same.
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PMID:Fish oil induced increase in walking distance, but not ankle brachial pressure index, in peripheral arterial disease is dependent on both body mass index and inflammatory genotype. 1760 Jun 95

Lameness is a major health issue and likely the single most common cause of pain and discomfort in dairy cattle. Appropriate treatment is delayed or neglected due, in part, to lack of reliable detection. Assessment of cows with lameness is currently limited to subjective visual scoring systems based on locomotion and posture abnormalities. These systems are unreliable to detect lameness, and therefore, a large number of cows remain undiagnosed. The objective of this research was to search for potential biomarkers for lameness-associated painful inflammatory foot lesions in dairy cattle using microarray-based gene expression profiling of peripheral blood mononuclear cells (PBMC). BOTL5 microarrays spotted in duplicate with cDNA representing bovine immune response genes were interrogated with cDNA samples in an eight-array, balanced complete block design with dye swap. Samples from eight lame cows with inflammatory foot lesions and from eight sound cows were pair-matched by age, weight, days in lactation, and pregnancy status at time of PBMC collection and directly compared with each other on individual arrays. Statistical analysis of resulting fluorescence intensity data revealed 31 genes that were putatively differentially expressed in lame versus sound cows (P<0.05). Of these, BLASTn analysis and gene ontology information showed that 28 genes had high similarity or homology to known human and/or rodent genes. Validation of 15 of these genes known to be important in inflammation and pain was carried out using relative quantitative real-time RT-PCR, which confirmed the up-regulation of interleukin (IL)-2 (12.68+/-1.47-fold increase) and IL-10 (2.39+/-0.55-fold increase), matrix metalloproteinase-13 (MMP-13) (10.44+/-1.14-fold increase), and chemokine C-C motif receptor-5 (CCR5) (5.26+/-1.05-fold increase), in lame relative to sound cows (P< or =0.05). Similarly, granulocyte-macrophage colony-stimulating factor receptor alpha chain precursor (GM-CSF-R-alpha) (2.30+/-0.63-fold increase) and IL-4 (2.06+/-0.59-fold increase) showed a tendency (P=0.10) for up-regulation in lame compared to sound cows. PBMC co-expression of IL-2, MMP-13, CCR5 and IL-10, and potentially IL-4 and GM-CSF-R-alpha appears to be a promising, objective sign of lameness-related inflammatory foot lesions in dairy cattle. In conclusion, this study revealed potential biomarkers of the presence of foot lesions that could boost diagnostic accuracy of lameness and, ultimately, help identify animals in need of pain relief.
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PMID:Gene expression profiling of peripheral mononuclear cells in lame dairy cows with foot lesions. 1767 48

The objectives of the present study were to evaluate the presence of antipolymer antibody (APA) seropositivity in 285 Italian patients affected by primary fibromyalgia (FM) and to verify whether APA levels correlate with disease severity and with cytokine levels.APA levels were determined on serum samples by an indirect ELISA kit that detects IgG APA. Cytokines (IL-1, IL-6, IL-8, IL-10 and TNFalpha) were measured by ELISA in plasma. The impact of FM on the quality of life was estimated using the Fibromyalgia Impact Questionnaire, while pain severity was evaluated using a visual analogic scale. Patients were also characterized by the presence of tiredness, stiffness, nonrestorative sleep, anxiety, depression, tension headache, irritable bowel syndrome, temporomandibular dysfunction and Raynaud's phenomena. Using a cut-off value of 30 U, APA-positive values were detected in 60 FM patients (21.05%) and in 15 healthy control individuals (15.00%) without significant differences among their levels or the percentage of seropositivity. FM patients with moderate and severe symptoms had slightly higher APA levels with respect to patients with mild symptoms. APA-seropositive patients exhibited significant correlations between APA levels and the Fibromyalgia Impact Questionnaire estimate (P = 0.042), tiredness (P = 0.003) and IL-1 levels (P = 0.0072). In conclusion, APA cannot be considered a marker of disease in Italian FM patients. The presence of APA, however, might permit the identification of a subset of FM patients with more severe symptoms and of patients who may respond differently to different therapeutic strategies.
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PMID:Antipolymer antibody in Italian fibromyalgic patients. 1782 28

Recent findings demonstrate that chemokines, and more specifically CC chemokine ligand 2 (CCL2 or monocyte chemoattractant protein-1), play a major role in pain processing. In the present study, we assess nociceptive responses of mice that overexpressed CCL2 under control of glial fibrillary acidic protein promoter (CCL2 tg). In models of acute nociception CCL2 tg mice demonstrated significantly enhanced nociceptive behavior relative to wild-type controls in responses to both thermal (hot plate) and chemical (formalin test) stimulus modalities. There were no differences in mechanical allodynia in the partial sciatic nerve ligation model, in terms of either magnitude or duration of the allodynic response; however, both groups responded to the maximal extent measurable. In a model of inflammatory pain, elicited by intraplantar administration of complete Freund's adjuvant (CFA), CCL2 tg mice displayed both greater edema and thermal hyperalgesia compared with control mice. In control mice, edema and hyperalgesia returned to baseline values 5-7 days post CFA. However, in CCL2 tg mice, thermal hyperalgesia was significantly different from baseline up to 3 weeks post CFA. Parallel to these enhanced behavioral responses CCL2 serum levels were significantly greater in CCL2 overexpressing mice and remained elevated 7 days post CFA. Consequently, proinflammatory cytokine mRNA expression (IL-1beta, IL-6, and TNFalpha) levels were greater in skin, dorsal root ganglia (DRG), and spinal cord, whereas the anti-inflammatory cytokine (IL-10) level was lower in skin and DRG in CCL2 overexpressing mice than in control mice. Taken together with data from CCR2-deficient mice, these present data confirm a key role of CCL2/CCR2 axis in pain pathways and suggest that inhibiting this axis may result in novel pain therapies.
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PMID:Mice overexpressing chemokine ligand 2 (CCL2) in astrocytes display enhanced nociceptive responses. 1787 Feb 46

Complex regional pain syndromes (CRPS) are characterized by persistent and severe pain after trauma or surgery. Neuro-immune alterations are assumed to play a pathophysiological role. Here we set out to investigate whether patients with CRPS have altered systemic pro- and anti-inflammatory cytokine profiles compared to controls on mRNA and protein level. We studied blood cytokine mRNA and protein levels of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF), interleukin-2 (IL-2) and IL-8 and the anti-inflammatory cytokines IL-4, IL-10, and transforming growth factor-beta1 (TGF beta 1) in 40 prospectively recruited patients with CRPS I, two patients with CRPS II, and 34 controls. Quantitative real-time PCR and enzyme linked immunosorbent assay were used. Additionally, the patients underwent quantitative sensory testing and were assessed with the McGill pain questionnaire and the Hospital anxiety and depression scale. Patients with CRPS had higher blood TNF and IL-2 mRNA levels (p=0.005; p=0.04) and lower IL-8 mRNA levels (p<0.001) than controls. The mRNA for the anti-inflammatory cytokines IL-4 and IL-10 was reduced in the patient group (p=0.004; p=0.006), whereas TGF beta 1 mRNA levels did not differ between groups. These results were paralleled by serum protein levels, except for TGF beta 1, which was reduced in patients with CRPS, and for IL-8, which gave similar protein values in both groups. Sensory testing showed a predominant loss of small fiber-related modalities in the patient group. The shift towards a pro-inflammatory cytokine profile in patients with CRPS suggests a potential pathogenic role in the generation of pain.
Pain 2007 Nov
PMID:Differential expression patterns of cytokines in complex regional pain syndrome. 1789 83

Although it is recognized that neurogenic influences contribute to progression of chronic inflammatory diseases, the molecular basis of neuroimmune interactions in the pathogenesis of chronic pancreatitis (CP) is not well defined. Here we report that responsiveness of peripheral blood mononuclear cells (PBMC) to the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is altered in CP. Expression of PACAP and its receptors in human CP was analyzed with quantitative RT-PCR, laser-capture microdissection, and immunohistochemistry. Regulation of PACAP expression was studied in coculture systems using macrophages and acinar cells. Responsiveness of donor and CP PBMC to PACAP was determined based on cytokine profiles and NF-kappaB activation of LPS- or LPS+PACAP-exposed cells. Although donor and CP PBMC responded equally to LPS, PACAP-mediated counteraction of LPS-induced cytokine response was switched from inhibiting TNF-alpha to decreasing IL-1beta and increasing IL-10 secretion. The change of PACAP-mediated anti-inflammatory pattern was associated with altered activation of NF-kappaB: compared with LPS alone, a combination of LPS and PACAP had no effect on NF-kappaB p65 nuclear translocation in CP PBMC, whereas NF-kappaB was significantly decreased in donor PBMC. According to laser-capture microdissection and coculture experiments, PBMC also contributed to generation of a PACAP-rich intrapancreatic environment by upregulating PACAP expression in macrophages encountering apoptotic pancreatic acini. The nociceptive status of CP patients correlated with pancreatic PACAP levels and with IL-10 bias of PACAP-exposed CP PBMC. Thus the ability of PBMC to produce and to respond to PACAP might influence neuroimmune interactions that regulate pain and inflammation in CP.
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PMID:Altered anti-inflammatory response of mononuclear cells to neuropeptide PACAP is associated with deregulation of NF-{kappa}B in chronic pancreatitis. 1796 62


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