Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Enkephalins are a biochemical pathway for endogenous analgesia. A number of compounds inhibit degradation of enkephalins within the body. One of these compounds, D-phenylalanine (DPA), has been shown to increase the pain threshold in animals. It is hypothesized that this naloxone reversible analgesia is induced by DPA blockage of enkephalin degradation by the enzyme carboxypeptidase A. Preliminary studies of chronic pain patients have shown a response rate to DPA from 32% to 75%. This study was a double-blind crossover evaluation of a randomized parallel design to determine the efficacy of DPA in 30 subjects with chronic pain from varied etiology which was unrelieved by multiple therapeutic interventions. Each patient received a stabilized therapeutic regimen during this study consisting of four weeks of either DPA 250 mg or lactose (placebo) orally four times a day. After four weeks the DPA and placebo groups were crossed over for an additional four weeks of treatment. Pain was quantified using a visual analog pain scale and a cold pressor test. Data from the pain questionnaires revealed more pain relief on DPA reported by 25% of the patients, more pain relief on placebo reported by 22% of the patients, and no difference in pain relief reported by 53% of the patients. Lowest pain level of the visual analog scale was reported by 47% of the patients on DPA and 53% on placebo. There appears to be no significant analgesic effect from D-phenylalanine in chronic pain patients when compared to placebo.
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PMID:Analgesic effectiveness of D-phenylalanine in chronic pain patients. 352 9

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), is of considerable interest in clinical urology. During the past decade, several new approaches have been made to discover its aetiology and pathophysiological mechanisms and to develop treatment modalities. The aetiology of CPPS has remained unresolved. Bacterial, chemical, urodynamic and immunological aetiologies have been suggested, but none of these has been conclusively proven. The histopathological changes in CP and CPPS are relatively well known, but the pathophysiological changes that lead to chronic inflammation and prolonged symptoms are still poorly understood. This review proposes an additional approach to the pathophysiology of CPPS. The concept of prostate tissue pressure is introduced as an objectively measurable parameter in evaluating the inflammatory process in CPPS. Chronic pain due to neurogenic inflammation and altered mast cell function is also discussed.
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PMID:Mechanisms of pain in chronic pelvic pain syndrome: influence of prostatic inflammation. 1270 Sep 22

This review summarizes the principal therapeutic responses to the preferential COX-2 NSAID, nimesulide, in treating musculo-skeletal joint symptoms and various acute and chronic pain conditions and the mode of action in relation to therapy in these states. In extensive studies in laboratory animal models and clinical trails in patients nimesulide has been found to have potent analgesic, anti-inflammatory and anti-pyretic activities. It is approved for use in over 50 countries worldwide (including those in the EU, South and Central America, China, India and some other South-East Asia) for the treatment of acute pain, the symptomatic treatment of painful osteoarthritis and primary dysmenorrhoea. Its mode of action in these states is related to the preferential inhibition of the production of cyclo-oxygenase-2 (COX-2) and other inflammatory mediators whose production is controlled by stimulation of cyclic-3 ,5'-adenosine monophosphate (cAMP); this means that nimesulide is a multi-factorial drug in controlling inflammation and pain. The adverse reaction profile of nimesulide is, in general, like that of other NSAIDs. It does, however, have relatively low occurrence of gastro-intestinal (GI) side effects which is related to its low propensity to inhibit the physiologically important COX-1 in the GI mucosa and important physicochemical properties (high pKa of 6.5 and lipophilicity) as well as inhibiting of mast cell derived histamine and acid secretion in the stomach. In contrast with the coxibs, nimesulide has not been found to have appreciable cardiovascular toxicity.
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PMID:Current status of the therapeutic uses and actions of the preferential cyclo-oxygenase-2 NSAID, nimesulide. 1698 92

Cannabis extracts and synthetic cannabinoids are still widely considered illegal substances. Preclinical and clinical studies have suggested that they may result useful to treat diverse diseases, including those related with acute or chronic pain. The discovery of cannabinoid receptors, their endogenous ligands, and the machinery for the synthesis, transport, and degradation of these retrograde messengers, has equipped us with neurochemical tools for novel drug design. Agonist-activated cannabinoid receptors, modulate nociceptive thresholds, inhibit release of pro-inflammatory molecules, and display synergistic effects with other systems that influence analgesia, especially the endogenous opioid system. Cannabinoid receptor agonists have shown therapeutic value against inflammatory and neuropathic pains, conditions that are often refractory to therapy. Although the psychoactive effects of these substances have limited clinical progress to study cannabinoid actions in pain mechanisms, preclinical research is progressing rapidly. For example, CB(1)mediated suppression of mast cell activation responses, CB(2)-mediated indirect stimulation of opioid receptors located in primary afferent pathways, and the discovery of inhibitors for either the transporters or the enzymes degrading endocannabinoids, are recent findings that suggest new therapeutic approaches to avoid central nervous system side effects. In this review, we will examine promising indications of cannabinoid receptor agonists to alleviate acute and chronic pain episodes. Recently, Cannabis sativa extracts, containing known doses of tetrahydrocannabinol and cannabidiol, have granted approval in Canada for the relief of neuropathic pain in multiple sclerosis. Further double-blind placebo-controlled clinical trials are needed to evaluate the potential therapeutic effectiveness of various cannabinoid agonists-based medications for controlling different types of pain.
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PMID:Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes. 1861 44

Although the pathophysiology of chronic urticaria is not fully understood, it is possible that dysfunctioning of peripheral cutaneous nerve fibres may be involved. It has also been suggested that fibromyalgia syndrome, a multi-symptomatic chronic pain condition, may be associated with alterations and dysfunctioning of peripheral cutaneous nerve fibres. The aim of this study was to determine whether patients with chronic urticaria are also affected by fibromyalgia syndrome. A total of 126 patients with chronic urticaria were investigated for fibromyalgia syndrome. An unexpectedly high proportion (over 70%) had fibromyalgia syndrome. The corresponding proportion for 50 control dermatological patients was 16%, which is higher than previously published data for the Italian general population (2.2%). It is possible that dysfunctional cutaneous nerve fibres of patients with fibromyalgia syndrome may release neuropeptides, which, in turn, may induce dermal microvessel dilatation and plasma extravasation. Furthermore, some neuropeptides may favour mast cell degranulation, which stimulates nerve endings, thus providing positive feedback. Chronic urticaria may thus be viewed in many patients, as a consequence of fibromyalgia syndrome; in fact, skin neuropathy (fibromyalgia syndrome) may trigger neurogenic skin inflammation (chronic urticaria).
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PMID:Chronic urticaria is usually associated with fibromyalgia syndrome. 1968 52

Pain is a complex subjective experience, associated with neurovegetative, affective and cognitive rapid changes. Biological, psychosocial and contextual factors may contribute. Chronic inflammation, of whatever cause, is the leading contributor to chronic pain. The mast cell directs both the inflammatory process and the shift to chronic pain, mediating through the production of Nerve Growth Factor (NGF) and other neurotrophic molecules. Women, in the fertile age, are biologically more vulnerable to chronic inflammation, as fluctuations of estrogens are agonist factors of mast cells degranulation, mostly in the premenstrual phase. Pain is defined as "nociceptive" when it indicates an ongoing damage; "neuropathic" when it becomes a disease per se. Chronic Pelvic Pain (CPP) indicates an invalidating, persistent or recurrent pelvic pain, persisting for more than 6 months. CPP is the main complaint of 10-15% of gynaecologic consultations, leading to 40% of diagnostic laparoscopies and 15% of hysterectomies. Comorbidity, i.e. the coexistence of pathologies and painful syndromes in different pelvic organs, is another common feature. Cystitis, vulvar vestibulitis, endometriosis, irritable bowel syndrome all play an important role and contribute to identifying the hyperactive mast cell and related chronic inflammation as the common pathophysiologic factor. The paper reviews nociception characteristics, the emerging role of mast cells, the pathophysiology of comorbidity, biological, psychosexual and contextual predictors, and stresses the need to move from a "hyperspecialistic" perspective to a multisystemic reading of CPP, with special attention to the urologic perspective.
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PMID:[Perception of chronic pelvic pain in women: predictors and clinical implications]. 2108 54

We have previously shown that the endogenous lipid palmitoylethanolamide (PEA) induced relief of neuropathic pain through an action upon receptors located on the nociceptive pathway. Recently, it has been proposed that immune cells, in particular mast cells, and microglia, by releasing algogen mediators interact with neurons to alter pain sensitivity thereby contributing to the development and maintenance of chronic pain states. The aim of this work was to explore whether the anti-nociceptive properties of PEA might be accompanied by modulation of these non-neuronal cells. Mice were subjected to a chronic constriction injury model of neuropathic pain and treated with PEA. The data show that at the earlier (3 days) time-point after nerve injury there was a substantial recruitment of mast cells whose activation was not yet pronounced. In contrast, at the later time point (8 days) there was no further increase in mast cell number, but rather a marked activation of these cells. An up-regulation of activated microglia was found in the spinal cord of neuropathic pain mice. PEA delayed mast cell recruitment, protected mast cells against degranulation and abolished the nerve growth factor increase in sciatic nerve concomitantly preserving the nerve from degeneration, while reducing microglia activation in the spinal cord. These findings support the idea that non-neuronal cells may be a valuable pharmacological target to treat neuropathic pain since the current neuronal-direct drugs are still unsatisfactory. In this context PEA could represent an innovative molecule, combining a dual analgesic activity, both on neurons and on nonneuronal cells.
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PMID:Non-neuronal cell modulation relieves neuropathic pain: efficacy of the endogenous lipid palmitoylethanolamide. 2339 19

Primate-specific Mas-related G protein-coupled receptors-X1 (MRGPR-X1) are highly enriched in dorsal root ganglia (DRG) neurons and induce acute pain. Herein, we analyzed effects of MRGPR-X1 on serum response factors (SRF) or nuclear factors of activated T cells (NFAT), which control expression of various markers of chronic pain. Using HEK293, DRG neuron-derived F11 cells and cultured rat DRG neurons recombinantly expressing human MRGPR-X1, we found activation of a SRF reporter gene construct and induction of the early growth response protein-1 via extracellular signal-regulated kinases-1/2 known to play a significant role in the development of inflammatory pain. Furthermore, we observed MRGPR-X1-induced up-regulation of the chemokine receptor 2 (CCR2) via NFAT, which is considered as a key event in the onset of neuropathic pain and, so far, has not yet been described for any endogenous neuropeptide. Up-regulation of CCR2 is often associated with increased release of its endogenous agonist chemokine ligand 2 (CCL2). We also found MRGPR-X1-promoted release of CCL2 in a human connective tissue mast cell line endogenously expressing MRGPR-X1. Thus, we provide first evidence to suggest that MRGPR-X1 induce expression of chronic pain markers in DRG neurons and propose a so far unidentified signaling circuit that enhances chemokine signaling by acting on two distinct yet functionally co-operating cell types. Given the important role of chemokine signaling in pain chronification, we propose that interruption of this signaling circuit might be a promising new strategy to alleviate chemokine-promoted pain.
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PMID:Human Mas-related G protein-coupled receptors-X1 induce chemokine receptor 2 expression in rat dorsal root ganglia neurons and release of chemokine ligand 2 from the human LAD-2 mast cell line. 2350 57

The involvement of serotonin (5-HT) in chronic pain mechanisms is established. 5-HT inhibits central painful stimuli, but recent data suggests that 5-HT could also enhance pain stimulus from the periphery, where mast cells play an important role. We aimed in our study to clarify the influence of selected tricyclic antidepressants (TCAs) on mast cell function: secretion, uptake, and reuptake of 5-HT, that could interfere with 5-HT levels and in this way contribute to the generation of pain. As an experimental model, we used isolated rat peritoneal mast cells and incubated them with selected TCAs (clomipramine, amitriptyline, doxepin, and imipramine) under different experimental conditions. 5-HT release, uptake, and reuptake were determined spectrofluorometrically. We showed that TCAs were able to inhibit 5-HT secretion from mast cells, as well as uptake of exogenous 5-HT and reuptake of secreted 5-HT back into mast cells. The effects of TCAs were concentration dependent; higher concentrations of TCAs inhibited the secretion of 5-HT induced by compound 48/80, whereas lower concentrations of TCAs inhibited 5-HT uptake. The most effective TCA was halogenated clomipramine. As TCAs are well introduced in chronic pain treatment, the insight into mechanisms of action is important for an understanding of their effect in various pain conditions.
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PMID:Chronic pain treatment: the influence of tricyclic antidepressants on serotonin release and uptake in mast cells. 2371 Jan 15

Changes in the regulation of connective tissue ATP-mediated mechano-transduction and remodeling may be an important link to the pathogenesis of chronic pain. It has been demonstrated that mast cell-derived histamine plays an important role in painful fibrotic diseases. Here we analyzed the involvement of ATP in the response of human subcutaneous fibroblasts to histamine. Acute histamine application caused a rise in intracellular Ca(2+) ([Ca(2+)]i) and ATP release from human subcutaneous fibroblasts via H1 receptor activation. Histamine-induced [Ca(2+)]i rise was partially attenuated by apyrase, an enzyme that inactivates extracellular ATP, and by blocking P2 purinoceptors with pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid) tetrasodium salt and reactive blue 2. [Ca(2+)]i accumulation caused by histamine was also reduced upon blocking pannexin-1 hemichannels with (10)Panx, probenecid, or carbenoxolone but not when connexin hemichannels were inhibited with mefloquine or 2-octanol. Brefeldin A, an inhibitor of vesicular exocytosis, also did not block histamine-induced [Ca(2+)]i mobilization. Prolonged exposure of human subcutaneous fibroblast cultures to histamine favored cell growth and type I collagen synthesis via the activation of H1 receptor. This effect was mimicked by ATP and its metabolite, ADP, whereas the selective P2Y1 receptor antagonist, MRS2179, partially attenuated histamine-induced cell growth and type I collagen production. Expression of pannexin-1 and ADP-sensitive P2Y1 receptor on human subcutaneous fibroblasts was confirmed by immunofluorescence confocal microscopy and Western blot analysis. In conclusion, histamine induces ATP release from human subcutaneous fibroblasts, via pannexin-1 hemichannels, leading to [Ca(2+)]i mobilization and cell growth through the cooperation of H1 and P2 (probably P2Y1) receptors.
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PMID:Histamine induces ATP release from human subcutaneous fibroblasts, via pannexin-1 hemichannels, leading to Ca2+ mobilization and cell proliferation. 2391 24


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