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

The innervation of the sphincter of Oddi (SO) has been extensively studied experimentally, but human studies have not been published, which is why this study was undertaken. Biopsies, taken by gastroscopy-biopsy forceps from duodenal epithelium of the papilla of Vater and from ampullary epithelium after sphincterotomy, did not demonstrate nerves and could not be used for studying SO innervation. Therefore SO specimens were obtained from brain-dead organ donors (N = 5) and from autopsies (N = 14). By staining with a myelin marker S-100, a rich network of nerves was demonstrated in SO. The occurrence of vasoactive intestinal polypeptide (VIP), peptide histidine-isoleucine (PHI) (or its immunologically similar human equivalent peptide histidine methioninamide, PHM), neuropeptide Y, calcitonin gene-related peptide (CGRP), galanin, substance P, enkephalin, bombesin, and somatostatin were studied by immunohistochemical technique. SO demonstrated immunoreactivity for VIP, PHI (PHM), neuropeptide Y, CGRP, galanin, somatostatin, substance P, and enkephalin, but no immunoreactivity was observed for bombesin. The SO immunoreactivity was similar in specimens from organ donors and from autopsies of victims of violence without pancreatobiliary diseases (N = 3) when the specimens were taken within 48 hr of death. Autopsy specimens of SO from subjects with gallstone disease (N = 5), recurrent pancreatitis (N = 3) or periampullary carcinoma (N = 3) also demonstrated similar immunoreactivity. We conclude that VIP-, PHI- (PHM-), neuropeptide Y-, CGRP-, galanin-, substance P-, somatostatin-, and enkephalin-like immunoreactivity occur in human SO. These neuropeptides may have role in the neural control of human SO function.
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PMID:Peptidergic innervation of human sphincter of Oddi. 831 11

Substance P, acting via the neurokinin 1 receptor (NK1R), plays an important role in mediating a variety of inflammatory processes. However, its role in acute pancreatitis has not been previously described. We have found that, in normal mice, substance P levels in the pancreas and pancreatic acinar cell expression of NK1R are both increased during secretagogue-induced experimental pancreatitis. To evaluate the role of substance P, pancreatitis was induced in mice that genetically lack NK1R by administration of 12 hourly injections of a supramaximally stimulating dose of the secretagogue caerulein. During pancreatitis, the magnitude of hyperamylasemia, hyperlipasemia, neutrophil sequestration in the pancreas, and pancreatic acinar cell necrosis were significantly reduced in NK1R-/- mice when compared with wild-type NK1R+/+ animals. Similarly, pancreatitis-associated lung injury, as characterized by intrapulmonary sequestration of neutrophils and increased pulmonary microvascular permeability, was reduced in NK1R-/- animals. These effects of NK1R deletion indicate that substance P, acting via NK1R, plays an important proinflammatory role in regulating the severity of acute pancreatitis and pancreatitis-associated lung injury.
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PMID:Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury. 953 12

Acute pancreatitis is an inflammatory disease, which varies in severity from mild to severe. Factors determining the severity of pancreatitis are not known. It is generally believed that the earliest events in the evolution of acute pancreatitis lead to premature intra-acinar cell activation of digestive zymogens and that those enzymes, once activated cause acinar cell injury. Recent studies have suggested that the ultimate severity of resulting pancreatitis may be determined by events which occur subsequent to acinar cell injury. These include inflammatory cell recruitment and activation as well as the generation and release of cytokines and other chemical mediators of inflammation. Recently, we have undertaken studies to elucidate the role of various inflammatory agents in determining the severity of pancreatitis. Results from these ongoing studies indicate that substance P acting via neurokinin-1 (NK1) receptors, chemokines interacting with CCR1 receptors and platelet activating factor play an important pro-inflammatory role in regulating the severity of pancreatitis and associated lung injury. On the other hand, complement factor 5a (C5a) acts as an anti-inflammatory agent during the development of pancreatitis.
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PMID:Pathophysiology of pancreatitis. Role of cytokines and other mediators of inflammation. 1002 28

Pancreatic oedema occurs early in the development of acute pancreatitis, and the overall extent of fluid loss correlates with disease severity. The tachykinin substance P (SP) is released from sensory nerves, binds to the neurokinin-1 receptor (NK1-R) on endothelial cells and induces plasma extravasation, oedema, and neutrophil infiltration, a process termed neurogenic inflammation. We sought to determine the importance of neurogenic mechanisms in acute pancreatitis. Pancreatic plasma extravasation was measured using the intravascular tracers Evans blue and Monastral blue after administration of specific NK1-R agonists/antagonists in rats and NK1-R(+/+)/(-/-) mice. The effects of NK1-R genetic deletion/antagonism on pancreatic plasma extravasation, amylase, myeloperoxidase (MPO), and histology in cerulein-induced pancreatitis were characterized. In rats, both SP and the NK1-R selective agonist [Sar(9) Met(O(2))(11)]SP stimulated pancreatic plasma extravasation, and this response was blocked by the NK1-R antagonist CP 96,345. Selective agonists of the NK-2 or NK-3 receptors had no effect. In rats, cerulein stimulated pancreatic plasma extravasation and serum amylase. These responses were blocked by the NK1-R antagonist CP 96,345. In wildtype mice, SP induced plasma extravasation while SP had no effect in NK1-R knockout mice. In NK1-R knockout mice, the effects of cerulein on pancreatic plasma extravasation and hyperamylasemia were reduced by 60%, and pancreatic MPO by 75%, as compared to wildtype animals. Neurogenic mechanisms of inflammation are important in the development of inflammatory oedema in acute interstitial pancreatitis.
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PMID:Substance P mediates inflammatory oedema in acute pancreatitis via activation of the neurokinin-1 receptor in rats and mice. 1082 77

Patients with acute pancreatitis may develop acute lung injury, manifest clinically as the adult respiratory distress syndrome. Most patients who die during the early stages of severe acute pancreatitis die either with or as a result of this lung injury. To explore the events which couple acute pancreatitis to lung injury, a number of recent studies have been performed in the author's laboratory using a variety of experimental models and interventions including gene-targeted deletion of chemokines, cytokines, specific receptors, and adhesion molecules. These studies have indicated that adhesion molecules such as intracellular adhesion molecule-1 (ICAM-1), neutrophils, platelet activating factor (PAF), substance P, and chemokines acting via the CCR-1 chemokine receptor play a pro-inflammatory role while complement factor C5a plays an anti-inflammatory role in pancreatitis and lung injury. Future studies will build on these observations to expand the list of pro- and anti-inflammatory coupling factors and explore the mechanisms by which they act to cause or prevent lung injury in acute pancreatitis.
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PMID:Relationship between pancreatitis and lung diseases. 1153 57

We examined whether the capsaicin vanilloid receptor-1 (VR1) mediates substance P (SP) release from primary sensory neurons in experimental pancreatitis. Pancreatitis was achieved by 12 hourly injections of caerulein (50 microg/kg ip) in mice. One group received capsazepine (100 micromol/kg sc), a competitive VR1 antagonist, at 4-h intervals. Neurokinin-1 receptor (NK1R) internalization in acinar cells, used as an index of endogenous SP release, was assessed by immunocytochemical quantification of NK1R endocytosis. The severity of pancreatitis was assessed by measurements of serum amylase, pancreatic myeloperoxidase (MPO) activity, and histological grading. Caerulein administration caused significant elevations in serum amylase and pancreatic MPO activity, produced histological evidence of pancreatitis, and caused a dramatic increase in NK1R endocytosis. Capsazepine treatment significantly reduced the level of NK1R endocytosis, and this was associated with similar reductions in pancreatic MPO activity and histological severity of pancreatitis. These results demonstrate that repeated caerulein stimulation causes experimental pancreatitis that is mediated in part by stimulation of VR1 on primary sensory neurons, resulting in endogenous SP release.
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PMID:Capsaicin vanilloid receptor-1 mediates substance P release in experimental pancreatitis. 1166 42

More than 10 years of intensive preclinical investigation of selective tachykinin (TK) receptor antagonists has provided a rationale to the speculation that peripheral neurokinin (NK)-1, -2 and -3 receptors may be involved in the pathophysiology of various human diseases at the visceral level. In the airways, despite promising effects in animal models of asthma, pilot clinical trials with selective NK-1 or -2 receptor antagonists in asthmatics have been ambiguous, whereas the potential antitussive effects of NK-1, -2 or -3 antagonists have not yet been verified in humans. In the gastrointestinal (GI) tract, irritable bowel syndrome (IBS) and pancreatitis are appealing targets for peripherally-acting NK-1 and -2 antagonists, respectively. In the genito-urinary tract, NK-1 receptor antagonists could offer some protection against nephrotoxicity and cytotoxicity induced by chemotherapeutic agents, whereas NK-2 receptor antagonists appear to be promising new agents for the treatment of neurogenic bladder hyperreflexia. Finally, there is preclinical evidence for hypothesising an effect of NK-3 receptor antagonists on the cardiovascular disturbance that characterises pre-eclampsia. Other more speculative applications are also mentioned.
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PMID:Peripheral tachykinin receptors as potential therapeutic targets in visceral diseases. 1278 71

Although pain is a cardinal feature of pancreatitis, its pathogenesis is poorly understood and treatment remains difficult. Nociceptive sensitization in several somatic pain models has been associated with activation of protein kinases including trkA, protein kinase C, and protein kinase A. We therefore tested the hypothesis that systemic treatment with a kinase inhibitor, k252a, known to inhibit all of these kinases would alleviate pain in an animal model of pancreatitis. Von Frey filament testing of somatic referral regions was evaluated as a method to measure referred pain in a rat model of acute necrotizing pancreatitis induced by L-arginine. Rats with pancreatitis showed increased sensitivity to abdominal stimulation with Von Frey filament. This referred mechanical sensitivity was associated with an 8-fold increase in levels of phosphorylated trkA in the pancreas and with significant up-regulation of both calcitonin gene-related peptide and preprotachykinin mRNA expression in thoracic dorsal root ganglia and with increased calcitonin gene-related peptide and substance P immunoreactivity in spinal cord segment T10. Treatment with the kinase inhibitor k252a suppressed the phosphorylation of trkA in the pancreas as well as reversed both the behavioral changes and the increase in neuropeptide expression associated with pancreatitis.
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PMID:Acute pancreatitis results in referred mechanical hypersensitivity and neuropeptide up-regulation that can be suppressed by the protein kinase inhibitor k252a. 1462 90

Substance P (SP) acting at the NK-1 neurokinin receptor has a well-documented role in the transmission and maintenance of nociceptive information. SP is found in the majority of fibers innervating the pancreas, and it is up-regulated after pancreatic inflammation. The aim of this study was to investigate the role of the NK-1 receptors in the maintenance of pancreatic nociception. Using a newly developed rat model of acute pancreatic nociception that persists for 1 week, the NK-1 receptor expression in the spinal cord and pancreas was examined using immunohistochemistry and Western blotting procedures. The effects of a specific NK-1 antagonist, CP99,994, on the behavioral manifestations of pancreatic nociception were determined. The antagonist was administered intraperitoneally and intrathecally to differentiate peripheral and central effects. Injection of CP-100,263, the inactive enantiomer of CP-99,994 was used as a control for nonspecific effects of the antagonist. Immunohistochemistry and Western blotting analysis revealed an up-regulation of the NK-1 receptor occurs in the pancreas but not at the spinal cord level. The NK-1 antagonist was able to attenuate the nociceptive behaviors in rats with pancreatitis when applied intraperitoneally with a short duration of effectiveness. Intrathecal application of the antagonist was ineffective. These results suggest the involvement of pancreatic NK-1 receptors in the maintenance of nociception during pancreatic inflammation.
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PMID:Attenuation of nociception in a model of acute pancreatitis by an NK-1 antagonist. 1500 76

Stimulation of primary sensory neurons produces local vasodilation, plasma extravasation, and pain and is due largely to the release of the tachykinins substance P and calcitonin-gene-related peptide. Pathological activation of sensory neurons and the inflammatory sequelae are known as neurogenic inflammation and appear to be important in many organ systems, including the pancreas. Factors that stimulate primary sensory neurons include hydrogen ions, heat, leukotrienes, arachidonic acid metabolites, bradykinin, and proteases such as trypsin, all of which may participate in the generation of acute pancreatitis. The current review examines the cellular and molecular mechanisms involved in sensory nerve activation within the pancreas and the potential contribution of neurogenic inflammation to the pathogenesis of pancreatitis.
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PMID:Neurogenic inflammation and pancreatitis. 1555 Jul 64


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