Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Urocortin (Ucn) is related to corticotropin-releasing hormone (CRH), and both are released in the brain under stress where they stimulate CRH 1 and 2 receptors (CRHR). Outside the brain, they may have proinflammatory actions through activation of mast cells, which are located perivascularly close to nerve endings and degranulate in response to acute psychological stress. Here, we report that a concentration of intradermal Ucn as low as 10 nM induced dose-dependent rat skin mast cell degranulation and increased vascular permeability. This effect appeared to be equipotent to that of calcitonin gene-related peptide and neurotensin. Ucn-induced skin vasodilation was inhibited by pretreatment with the mast cell stabilizer disodium cromoglycate (cromolyn) and was absent in the mast cell-deficient W/Wv mice. The selective nonpeptide CRH receptor 1 antagonist, antalarmin and the nonselective peptide antagonist astressin both reduced vascular permeability triggered by Ucn but not that by Substance P or histamine. In contrast, the peptide antagonist alpha-helical CRH-(9-41) reduced the effect of all three. The vasodilatory effect of Ucn was largely inhibited by pretreatment with H1 receptor antagonists, suggesting that histamine is the major mediator involved in vitro. Neuropeptide depletion of sensory neurons, treatment with the ganglionic blocker hexamethonium, or in situ skin infiltration with the local anesthetic lidocaine did not affect Ucn-induced vascular permeability, indicating that its in situ effect was not mediated through the peripheral nervous system. These results indicate that Ucn is one of the most potent triggers of rat mast cell degranulation and skin vascular permeability. This effect of Ucn may explain stress-induced disorders, such as atopic dermatitis or psoriasis, and may lead to new forms of treatment.
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PMID:Potent mast cell degranulation and vascular permeability triggered by urocortin through activation of corticotropin-releasing hormone receptors. 1002 77

Many skin disorders, such as atopic dermatitis and psoriasis, worsen during stress and are associated with increased numbers and activation of mast cells which release vasoactive, nociceptive, and proinflammatory mediators. Nontraumatic acute psychological stress by immobilization has been shown to induce mast cell degranulation in the rat dura and colon. Moreover, intradermal injection of corticotropin-releasing hormone (CRH) or its analogue urocortin (10(-5)-10(-7) M) induced skin mast cell degranulation and increased vascular permeability. Here, we investigated the effect of acute immobilization stress on skin mast cell degranulation by light microscopy and electron microscopy. Immobilization for 30 min resulted (P < 0.05) in degranulation of 40.7 +/- 9.1% of skin mast cells compared to 22.2 +/- 7.3% in controls killed by CO(2) or 17.8 +/- 2.4% in controls killed by pentobarbital. Pretreatment intraperitoneally (ip) with antiserum to CRH for 60 min prior to stress reduced (P < 0.05) skin mast cell degranulation to 21.0 +/- 3. 3%. Pretreatment with the neurotensin (NT) receptor antagonist SR48692 reduced (P < 0.05) mast cell degranulation to 12.5 +/- 3.4%, which was significantly (P < 0.05) below control levels. In animals treated neonatally with capsaicin to deplete their sensory neurons of their neuropeptides, such as substance P (SP), mast cell degranulation due to immobilization stress was reduced to about 15%. This is the first time that stress has been shown to trigger skin mast cell degranulation, an action not only dependent on CRH, but apparently also involving NT and SP. These findings may have implications for the pathophysiology and possible therapy of neuroinflammatory skin disorders such as atopic dermatitis, neurogenic pruritus, or psoriasis, which are induced or exacerbated by stress.
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PMID:Acute immobilization stress triggers skin mast cell degranulation via corticotropin releasing hormone, neurotensin, and substance P: A link to neurogenic skin disorders. 1046 24

Several inflammatory skin conditions, including atopic dermatitis (AD) and psoriasis, are exacerbated by stress. Recent evidence suggests that crosstalk between mast cells, neurons and keratinocytes might be involved in such exacerbation. Mast cells are distributed widely in the skin, are present in increased numbers in AD and are located in close proximity to substance P- or neurotensin-containing neurons. Corticotropin-releasing factor (CRF), its structurally related peptide urocortin (Ucn) and their receptors are also present in the skin and their levels are increased following stress. Human mast cells synthesize and secrete both CRF and Ucn in response to immunoglobulin E receptor (FcepsilonRI) crosslinking. Mast cells also express CRF receptors, activation of which leads to the selective release of cytokines and other pro-inflammatory mediators. Thus, we propose that CRF receptor antagonists could be used together with natural molecules, such as retinol and flavonoids, to inhibit mast cell activation and provide new therapeutic options for chronic inflammatory conditions exacerbated by stress.
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PMID:Mast cells as targets of corticotropin-releasing factor and related peptides. 1549 78

Osteoarthritis (OA) is one of the most common and disabling chronic joint disorders affecting horses, dogs and humans. Synovial inflammation or synovitis is a frequently observed phenomenon in osteoarthritic joints and contributes to the pathogenesis of OA through formation of various catabolic and pro-inflammatory mediators altering the balance of cartilage matrix degradation and repair. Catabolic mediators produced by the inflamed synovium include pro-inflammatory cytokines, nitric oxide, prostaglandin E(2) and several neuropeptides, which further contribute to the pathogenesis of OA by increasing cartilage degradation. Recent studies suggest that substance P, corticotropin-releasing factor, urocortin and vasoactive intestinal peptide may also be involved in OA development, but the precise role of these neuropeptides in the pathogenesis of OA is not known. Since increased production of matrix metalloproteinases by the synovium is stimulated by pro-inflammatory cytokines, future anti-inflammatory therapies should focus on the synovium as a means of controlling subsequent inflammatory damage.
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PMID:The contribution of the synovium, synovial derived inflammatory cytokines and neuropeptides to the pathogenesis of osteoarthritis. 1791 Oct 37

This article summarizes the proceedings of a symposium held at the conference on "Alcoholism and Stress: A Framework for Future Treatment Strategies" in Volterra, Italy, May 6-9, 2008. Chaired by Markus Heilig and Roberto Ciccocioppo, this symposium offered a forum for the presentation of recent data linking neuropetidergic neurotransmission to the regulation of different alcohol-related behaviors in animals and in humans. Dr. Donald Gehlert described the development of a new corticotrophin-releasing factor receptor 1 antagonist and showed its efficacy in reducing alcohol consumption and stress-induced relapse in different animal models of alcohol abuse. Dr. Andrey Ryabinin reviewed recent findings in his laboratory, indicating a role of the urocortin 1 receptor system in the regulation of alcohol intake. Dr. Annika Thorsell showed data supporting the significance of the neuropeptide Y receptor system in the modulation of behaviors associated with a history of ethanol intoxication. Dr. Roberto Ciccocioppo focused his presentation on the nociceptin/orphanin FQ (N/OFQ) receptors as treatment targets for alcoholism. Finally, Dr. Markus Heilig showed recent preclinical and clinical evidence suggesting that neurokinin 1 antagonism may represent a promising new treatment for alcoholism. Collectively, these investigators highlighted the significance of neuropeptidergic neurotransmission in the regulation of neurobiological mechanisms of alcohol addiction. Data also revealed the importance of these systems as treatment targets for the development of new medication for alcoholism.
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PMID:Stress-related neuropeptides and alcoholism: CRH, NPY, and beyond. 1991 92

In recent years, studies have advocated neuropeptide systems as modulators for the behavioral states found in mood disorders such as depression and anxiety disorders. Neuropeptides have been tested in traditional animal models and screening procedures that have been validated by known antidepressants and anxiolytics. However, it has become clear that although these tests are very useful, neuropeptides have distinct behavioral effects and dose-dependent characteristics, and therefore, use of these tests with neuropeptides must be done with an understanding of their unique characteristics. This review will focus on the behavioral actions of neuropeptides and their synthetic analogs, particularly in studies utilizing various preclinical tests of depression and anxiety. Specifically, the following neuropeptide systems will be reviewed: corticotropin-releasing factor (CRF), urocortin (Ucn), teneurin C-terminal associated peptide (TCAP), neuropeptide Y (NPY), arginine vasopressin (AVP), oxytocin, the Tyr-MIF-1 family, cholecystokinin (CCK), galanin, and substance P. These neuropeptide systems each have a unique role in the regulation of stress-like behavior, and therefore provide intriguing therapeutic targets for mood disorder treatment.
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PMID:Behavioral effects of neuropeptides in rodent models of depression and anxiety. 2002 11

Major depression, with its strikingly high prevalence, is the most common cause of disability in communities of Western type, according to data of the World Health Organization. Stress-related mood disorders, besides their deleterious effects on the patient itself, also challenge the healthcare systems with their great social and economic impact. Our knowledge on the neurobiology of these conditions is less than sufficient as exemplified by the high proportion of patients who do not respond to currently available medications targeting monoaminergic systems. The search for new therapeutical strategies became therefore a "hot topic" in neuroscience, and there is a large body of evidence suggesting that brain neuropeptides not only participate is stress physiology, but they may also have clinical relevance. Based on data obtained in animal studies, neuropeptides and their receptors might be targeted by new candidate neuropharmacons with the hope that they will become important and effective tools in the management of stress related mood disorders. In this review, we attempt to summarize the latest evidence obtained using animal models for mood disorders, genetically modified rodent models for anxiety and depression, and we will pay some attention to previously published clinical data on corticotropin releasing factor, urocortin 1, urocortin 2, urocortin 3, arginine-vasopressin, neuropeptide Y, pituitary adenylate-cyclase activating polypeptide, neuropeptide S, oxytocin, substance P and galanin fields of stress research.
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PMID:Role of neuropeptides in anxiety, stress, and depression: from animals to humans. 2421 Jan 38

Exogenous administration of substance P (SP) exerts anorexigenic effects in both chicks and rats, but the central mechanism mediating this response is poorly understood. Therefore, this study was designed to elucidate mechanisms of SP-induced anorexia using chicks as models. Chicks that received intracerebroventricular (ICV) injections of SP dose-dependably reduced their food intake with no effect on water intake. Next, the diencephalon was isolated from SP-injected chicks and mRNA expression of neuropeptide Y (NPY), corticotropin releasing factor (CRF), urocortin 3 (UCN 3) and CRF receptors were measured but were not affected. When measured in the hypothalamus, mRNA abundance of these and NPY receptors, urotensin 2 (UTS2) and melanocortin receptor 4 (MCR4) were not affected by SP-injection. Quantification of c-Fos immunoreactivity in appetite-associated hypothalamic nuclei demonstrated that the paraventricular nucleus (PVN) was activated in SP-injected chicks. Finally, in the PVN isolated from SP-injected chicks, there was increased expression of UTS2 mRNA while CRF and UCN3 were not affected. Thus, the anorexigenic effects of SP appear to be mediated by PVN activation and may involve UTS2.
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PMID:Substance P is associated with hypothalamic paraventricular nucleus activation that coincides with increased urotensin 2 mRNA in chicks. 2500 52