UNIPROT:P20366 - FACTA Search

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Query: UNIPROT:P20366 (substance P)
21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The involvement of bradykinin, 5-hydroxytryptamine, substance P and prostanoids in the hyperalgesia elicited by collagenase in rat paw was investigated. Collagenase (100 micrograms) induced a slight hyperalgesia in kininogen deficient rats in comparison with the behavioural response obtained in normal rats. Lisinopril (10(-5) M), and angiotensin-converting enzyme inhibitor, increased the duration of the hyperalgesia elicited in normal rats. Ondansetron (0.5 to 5 mumol/kg), a 5-HT3 antagonist, suppressed the hyperalgesia as did methysergide (1.1 to 11 mumol/kg), a mixed 5-HT1 and 5-HT2 receptor antagonist. However, the hyperalgesia was not modified by RP 67580 (1.8 to 18 mumol/kg), a NK1 receptor antagonist, and was only slightly delayed by indomethacin (2 mg/kg), a cyclo-oxygenase inhibitor. The oedema-promoting effect of 5-HT (6 nmol) was inhibited by methysergide but not by ondansetron. The swelling induced by collagenase in rat paw was reduced by methysergide but not by ondansetron. We conclude that the behavioural response induced by collagenase depends on an interactions between bradykinin and 5-HT. Prostanoids play a minor role in the beginning of the reaction whereas substance P is not significantly involved in this hyperalgesia.
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PMID:Involvement of 5-hydroxytryptamine and bradykinin in the hyperalgesia induced in rats by collagenase from Clostridium histolyticum. 915 Dec 93

To characterize the inflammatory effect of spinorphin, an endogenous peptide purified from bovine spinal cord, its effects on chemotaxis, O2- generation, and exocytosis by N-formylmethionyl-leucyl-phenylalanine (FMLP)-stimulated human neutrophils (PMNs) in vitro were examined. At 10 microM, spinorphin significantly inhibited chemotaxis by FMLP-stimulated PMNs. Spinorphin at 100 microM also inhibited both O2- generation and exocytosis of beta-glucuronidase and collagenase by FMLP-stimulated PMNs. The mechanisms by which spinorphin inhibits these PMN functions were examined further. Spinorphin markedly suppressed the binding of FML[3H]P to its receptor on PMNs, as observed in a binding assay. However, other neuropeptides that were examined (angiotensin II and substance P) had no effect on FML[3H]P binding, suggesting the possibility that spinorphin plays a specific role in the inhibition of the binding between FMLP and its receptor. The suppression of FMLP binding also caused a decrease of the FMLP-induced intracellular calcium concentration [Ca2+]i, which acts as a second messenger leading to PMN functions. These results suggest that spinorphin may be a new endogenous inflammation-regulatory peptide that modulates the interaction of FMLP with its receptor.
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PMID:Inhibitory effects of spinorphin, a novel endogenous regulator, on chemotaxis, O2- generation, and exocytosis by N-formylmethionyl-leucyl-phenylalanine (FMLP)-stimulated neutrophils. 931 Mar 46

We investigated the secretion of the matrix metalloproteinases, interstitial collagenase (matrix metalloproteinase-1), gelatinase A (matrix metalloproteinase-2) and stromelysin-1 (matrix metalloproteinase-3) in human synovial fibroblasts after stimulation with the neuropeptide substance P. Human synovial fibroblasts were stimulated with substance P or interleukin-1 beta (IL-1 beta). In the cell culture media gelatinase A, interstitial collagenase and stromelysin-1 were identified and their activities towards different substrates were determined. Substance P in synovial fibroblasts induced an increase in the overall matrix metalloproteinase activity towards the dinitrophenyl-labelled peptide by 85%, against an increase of 124% after stimulation with IL-1 beta. In case of substance P stimulation, the increase in activity reflects a significantly enhanced secretion of gelatinase A, whereas no significant increase of stromelysin-1 and collagenase secretion could be observed. The matrix metalloproteinase pattern showing the highest gelatinase A secretion was obtained after stimulation with substance P. This pattern was very pronounced and differed very clearly from the pattern seen after IL-1 beta stimulation which caused a significant rise in collagenase and stromelysin-1 activity. We assume that distinct stimulation pathways are involved and that the neuropeptide (substance P), which is always present in the inflamed joint, plays its own and separate role in proliferative processes leading to the cartilage destruction.
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PMID:Substance P induces the secretion of gelatinase A from human synovial fibroblasts. 935 27

Explants of tissue derived from the medial collateral ligament (MCL) of normal and pregnant NZW rabbits cultured in the presence of substance P (SP), calcitonin gene-related peptide (CGRP), or both neuropeptides were found to have altered mRNA levels for a number of relevant molecules. Using a very efficient RNA isolation method, semi-quantitative RT-PCR and rabbit-specific primers, mRNA for growth factors (TGFbeta, bFGF, IGF-2, ET-1), cytokines (IL-1, TNF), enzymes (COX-2, iNOS), metalloproteinases (collagenase, stromelysin) and metalloproteinase inhibitors (TIMP-1, TIMP-2) were assessed after culture with or without neuropeptide. The results indicate that SP was effective in lowering mRNA levels for all of the molecules assessed in RNA from normal ligaments except IL-1beta, IGF-2 and TIMP-1, for which there was no significant effect. Similarly, CGRP was effective in lowering mRNA levels for all molecules except TNF, ET-1 and the TIMPs. The extent of the lowering of mRNA levels was both molecule-specific and neuropeptide-specific. When the experiments were repeated with ligament tissue from pregnant animals, a very different pattern of responsiveness to the neuropeptides was observed. While mRNA levels for 9/12 genes assessed were significantly affected by SP when normal MCL tissue was investigated, pregnancy abolished all significant responsiveness to this neuropeptide except for iNOS mRNA levels. In the case of iNOS mRNA, SP induced an increase in the steady-state levels, the opposite to what was observed with tissue from non-pregnant animals. For CGRP and SP+CGRP, tissue from pregnant animals was still responsive, but the pattern of responsiveness was changed from strictly a lowering of steady-state mRNA levels to elevations in mRNA levels for a number of genes. These findings indicate that mRNA levels for a number of genes can be influenced by neuropeptides known to be in ligaments. Thus, neuropeptides likely are important regulators of ligament cell metabolism. As the responsiveness to SP was nearly completely abolished during pregnancy, neuroregulatory influences mediated by this peptide are altered in the pregnant female. This loss of responsiveness to SP may also be one aspect of the analgesia associated with pregnancy.
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PMID:Pregnancy alters the in vitro responsiveness of the rabbit medial collateral ligament to neuropeptides: effect on mRNA levels for growth factors, cytokines, iNOS, COX-2, metalloproteinases and TIMPs. 978 99

A cellular suspension from rat submandibular glands was prepared with collagenase. The intracellular pH (pHi) was estimated with 2',7'-bis-(2-carboxy-ethyl)-5(6)-carboxyfluorescein (BCECF). After exposure to NH4Cl, the pHi transiently increased (diffusion of NH3) and then dropped (influx of NH4+). Isoproterenol increased 2.5-fold the rate of NH4+ influx; bumetanide, an inhibitor of the Na+-K+-2Cl(-)-cotransporter blocked the response to isoproterenol, confirming that the beta-adrenergic agonist stimulated the cotransporter. Forskolin (1 micromol/L) mimicked the response to isoproterenol. VIP (1 nmol/L(-1) micromol/L) also increased the activity of the cotransporter. Cyclic AMP rather than calcium was the mediator of this activation since 1) carbachol which increased the [Ca2+]i fivefold increased the uptake of NH4+ by only 50%; 2) only high concentrations of VIP significantly increased the [Ca2+]i; 3) incubation in the presence of EGTA had no effect on the response to VIP; 4) low concentrations (nmol/L) of the neuropeptide increased the intracellular level of cAMP; and 5) the stimulation of the cotransporter by VIP, forskolin, and isoproterenol was inhibited by H8, an inhibitor of cAMP-dependent protein kinase. It is concluded that the Na+-K+-2Cl(-)-cotransporter of rat submandibular glands is activated by isoproterenol, forskolin, and neuropeptides of the VIP family by a mechanism involving cAMP-dependent processes. The activation of the cotransporter by VIP could partly explain the potentiating effect of VIP on the response to sialagogues like substance P or muscarinic agonists.
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PMID:Activation of the Na+-K+(NH4+)-2Cl(-)- cotransporter from rat submandibular glands in response to VIP. 988 83

The activity and/or expression of the mitogen-activated protein kinases c-Jun N-terminal kinase 1, p38 and extracellular signal-regulated kinases 1/2, as well as their substrates, the transcription factors c-Jun and activating transcription factor-2, were examined following systemic application of kainate in the cortex and hippocampus of the adult rat brain. The protein expression levels of all three mitogen-activated protein kinases remained constant during the observation period. Unexpectedly, c-Jun N-terminal kinase 1 was the only mitogen-activated protein kinase activated in this model of excitotoxicity, its activity raised from between 1 and 3 h moderate basal to maximal levels between 6 and 12 h. In contradistinction, activity of extracellular signal-regulated kinases 1/2 fell from their substantial basal levels and did not recover; activity of p38 was characterized by a high basal level that almost entirely disappeared and did not return to basal levels even 10 days after kainate application. c-Jun protein was rapidly expressed, with a maximum after 3 h and a slow decline after 12 h. Supershift assays revealed that, during the early induction phase of the c-jun gene, the proximal activator protein-1 (jun1) site of the c-jun promoter was mainly occupied by the constitutively expressed activating transcription factor-2, whereas the late induction correlated with the predominant binding of c-Jun and, to a lesser extent, activating transcription factor-2 to the distal activator protein-1 (jun2) site. The time-course of the N-terminal phosphorylation of c-Jun as determined by immunocytochemistry paralleled the activity of c-Jun N-terminal kinase 1 and showed a compartment-specific regulation between 3 and 12 h. A second set of supershift experiments demonstrated that c-Jun, but not activating transcription factor 2, bound to activator protein-1 sites in the promoter of substance P and collagenase genes, but not of the cyclo-oxygenase-2 gene. Our results demonstrate that activation of c-Jun N-terminal kinase 1, phosphorylation of c-Jun and selective occupation of the c-jun promoter by activating transcription factor-2 or c-Jun are part of the neuronal response following excitotoxicity that is considered as the mechanism for neuronal apoptosis in vivo. Some of these findings differ substantially from in vitro experiments and underline the necessity to analyse the neuronal stress pathways in the adult brain.
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PMID:Activity and expression of JNK1, p38 and ERK kinases, c-Jun N-terminal phosphorylation, and c-jun promoter binding in the adult rat brain following kainate-induced seizures. 1036 4

The sensitivity to cholesterol depletion of calcium handling by rat submandibular glands was investigated. The glands were digested with collagenase. After homogenization, the lysate was extracted at 4 degrees C with 0.5% Triton X-100 and the extract was submitted to an ultracentrifugation in a sucrose discontinuous gradient. A population of detergent-resistant membranes (DRM) was collected at the 5%-35% interface. The DRM had a higher content of cholesterol, saturated and long-chain fatty acids. Caveolin-1 and alpha(q/11) were located in these membranes. They were more ordered than vesicles from total cellular lysate as determined by anisotropy measurement. They disappeared after cholesterol extraction with methyl-beta-cyclodextrin (MCD). Exposure of the cellular suspension with MCD nearly abolished the response to carbachol, epinephrine, and substance P and inhibited the activation of phospholipase C (PLC) by these agonists and by sodium fluoride. MCD did not affect the mobilization of intracellular pools of calcium by thapsigargin. It increased the uptake of extracellular calcium or barium and did not inhibit the uptake of calcium after depletion of the intracellular stores of this ion. From these results, it is concluded that Triton X-100 can extract a fraction of membrane resistant to detergents. Treatment of the cells with MCD disrupts these membranes. The coupling between the heterotrimeric GTP-binding protein G(q/11) and poly-phosphoinositide-specific PLC is affected by disruption of these membrane fractions. At the opposite, the store-operated calcium channel (SOCC) is not affected by DRM-disruption.
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PMID:Cholesterol depletion perturbs calcium handling by rat submandibular glands. 1552 Oct 67

Adenosine (ADO) is an endogenous purine nucleoside that functions as an extracellular signalling molecule. It is released locally at sites of cellular trauma, and acts on specific cell-surface purinergic receptors (termed P1 receptors) near its site of release to exert its effects. Four subtypes of the P1 family of G-protein-coupled receptors have been identified and cloned: A1, A2A, A2B and A3. A considerable body of evidence, including experimental animal data and preliminary clinical reports, indicates that ADO is involved in modulating endogenous antinociceptive processes in the brain and spinal cord. ADO analogues provide analgesic activity after systemic or spinal administration in a broad spectrum of animal pain models. In addition, iv. ADO infusion has shown benefit in human pain states. The spinal cord is a key site for ADO-mediated modulation of nociception. ADO is well known to act as an inhibitory neuromodulator in the central and peripheral nervous system, and it may act to control N-methyl-D-aspartate (NMDA)- and substance P-mediated events in nociception and central sensitisation at the spinal level. ADO is also released at sites of inflammation and it exerts anti-inflammatory effects via multiple mechanisms involving several cell types. These include effects on neutrophil function, endothelial cell permeability, in vivo and in vitro release of tumour necrosis factor (TNF-alpha and collagenase expression in synoviocytes. Accordingly, ADO analogues are effective in several animal models of inflammation, including the rat adjuvant arthritis model. Several therapeutic approaches to pain and inflammation, based on mimicking or modulating the effects of endogenous ADO, are currently under preclinical and clinical investigation. These include the use of ADO itself, the use of direct-acting ADO receptor agonists and the use of agents designed to modulate the levels and, therefore, the actions of ADO in the extracellular space (ADO kinase (AK) inhibitors). Data emerging in the next several years should indicate whether these strategies represent a therapeutically useful new approach to analgesia and inflammation.
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PMID:Adenosine modulation: a novel approach to analgesia and inflammation. 1599 91

Substance P is involved in inflammatory processes, but its effect on extracellular matrix metabolism has not been studied; therefore, the authors evaluated its effect on collagen synthesis and degradation, expression of pro-alpha1(I) collagen, matrix metalloproteinase-1 and -2, and tissue inhibitor of metalloproteinase-1 and -2 in normal human lung fibroblast strains. Substance P induced a decrease in collagen biosynthesis, concomitant to a down-regulation of pro-alpha1(I) collagen mRNA. In contrast, an increase in collagen degradation was observed, accompanied with an up-regulation of matrix metalloproteinase-1. Substance P did not influence tissue inhibitor of metalloproteinase-1 and -2 or matrix metalloproteinase-2 expression. The results suggest that substance P participates in extracellular matrix metabolism.
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PMID:Substance P up-regulates matrix metalloproteinase-1 and down-regulates collagen in human lung fibroblast. 1755 77

The authors tested whether macrophage metalloelastase (MMP-12) and substance P (SP) were increased in the cigarette smoke (CS)-exposed female C3H/HeN mice with hypercapnic emphysema. The authors found that as compared to control (filtered air), 16 weeks of CS exposure significantly up-regulated mRNA and protein levels of MMP-12, the ratio of MMP-12/tissue inhibitor of matrix metalloproteinase-1, and SP/preprotachykinin-A (a precursor to SP) in the lungs. Importantly, a significant correlation was found between MMP-12 and SP, and between MMP-12/SP and the degrees of hypoxemia/hypercapnia denoted in CS-exposed mice. These data suggest a possible involvement of SP and MMP-12 in the pathogenesis of severe COPD.
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PMID:Cigarette smoke-induced hypercapnic emphysema in C3H mice is associated with increases of macrophage metalloelastase and substance P in the lungs. 1762 Jan 83

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