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)

Tachykinin NK2 receptors are expressed in the gastrointestinal tract of both laboratory animals and humans. Experimental data indicate a role for these receptors in the regulation of intestinal motor functions (both excitatory and inhibitory), secretions, inflammation and visceral sensitivity. In particular, NK2 receptor stimulation inhibits intestinal motility by activating sympathetic extrinsic pathways or NANC intramural inhibitory components, whereas a modulatory effect on cholinergic nerves or a direct effect on smooth muscle account for the NK2 receptor-mediated increase in intestinal motility. Accordingly, selective NK2 receptor antagonists can reactivate inhibited motility or decrease inflammation- or stress-associated hypermotility. Intraluminal secretion of water is increased by NK2 receptor agonists via a direct effect on epithelial cells, and this mechanism is active in models of diarrhoea since selective antagonists reverse the increase in faecal water content in these models. Hyperalgesia in response to intraluminal volume signals is possibly mediated through the stimulation of NK2 receptors located on peripheral branches of primary afferent neurones. NK2 receptor antagonists reduce the hyper-responsiveness that occurs following intestinal inflammation or application of stressful stimuli to animals. Likewise, NK2 receptor antagonists reduce intestinal tissue damage induced by chemical irritation of the intestinal wall or lumen. In healthy volunteers, the selective NK2 antagonist nepadutant reduced the motility-stimulating effects and irritable bowel syndrome-like symptoms triggered by intravenous infusion of neurokinin A, and displayed other characteristics that could support its use in patients. It is concluded that blockade of peripheral tachykinin NK2 receptors should be considered as a viable mechanism for decreasing the painful symptoms and altered bowel habits of irritable bowel syndrome patients.
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PMID:Tachykinin NK2 receptor antagonists for the treatment of irritable bowel syndrome. 1503 22

The peptide substance P and its tachykinin receptor, neurokinin-1 (NK1), have been the focus of considerable research for their role in a variety of both central and peripheral diseases. Recent preclinical data, as well as relevant clinical findings, support the potential therapeutic value of NK1 receptor antagonists in centrally mediated disease states, including anxiety and depression. In addition, a separate body of literature supports the use of NK1 receptor antagonists as inhibitors of centrally mediated emetic and cough responses. The role of NK1 receptor antagonists as analgesic agents with potential to treat migraine headache has also been investigated. NK1 receptors are also found in a number of peripheral regions, including the bladder, gastrointestinal tract and bone marrow. Preclinical models have been employed to address the potential therapeutic uses for NK1 receptor antagonists in diseases associated with inflammatory responses, including asthma, irritable bowel syndrome and cystitis of the bladder. Finally, other more recent publications suggest a role for NK1 receptor antagonists as tumour suppressants and haematopoietic agents. These applications for NK1 receptor antagonists are discussed in this review.
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PMID:Potential therapeutic targets for neurokinin-1 receptor antagonists. 1515 33

The aim was to assess the roles of gut hormones and immune dysfunction in irritable bowel. In Study I, rectal mucosal samples examined blindly showed no histological evidence of inflammation in 16 irritable bowel patients compared to 17 healthy controls. The proinflammatory mediators interleukin-1beta and prostaglandin E2 also failed to show evidence of inflammation. Vasoactive intestinal peptide was elevated in irritable bowel (P = 0.01), but substance P, calcitonin gene-related peptide, and somatostatin levels were similar to control values. In Study II, 30 irritable bowel patients had elevated (P = 0.002) plasma concentrations of vasoactive intestinal peptide compared to 30 controls, and peptide levels were unrelated to whether the patient's predominant bowel habit was constipation, diarrhea, or both in alternation. In conclusion, no evidence of inflammation was detected in irritable bowel patients, but elevated vasoactive intestinal peptide concentrations were observed in both studies and might represent a potential diagnostic tool for irritable bowel syndrome.
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PMID:Elevated vasoactive intestinal peptide concentrations in patients with irritable bowel syndrome. 1538 52

The 5-HT3 receptor is a ligand-gated cation channel located in the central and peripheral nervous system; it has also been detected on a variety of other cells. In the periphery, it is found on autonomic neurons and on neurons of the sensory and enteric nervous system. In the CNS, the 5-HT3 receptor has been localized in the area postrema, nucleus tractus solitarii, nucleus vaudatus, nucleus accumbens, amygdala, hippocampus, entorhinal, frontal, cingulate cortex, and in the dorsal horn ganglia. Further extraneuronal locations include among others lymphocytes, monocytes, and foetal tissue. 5-HT3 receptors modulate the release of neurotransmitters and neuropeptides like dopamine, cholecystokinin, acetylcholine, GABA, substance P, and serotonin itself. They have been demonstrated to be involved in sensory transmission, regulation of autonomic functions, integration of the vomiting reflex, pain processing and control of anxiety. While the physiologic functions of the 5-HT3 receptor are discrete and difficult to detect, it plays a key role in certain pathologic situations related to increased serotonin release. Clinical development of 5-HT3 receptor antagonists revealed a remarkable range of activities. 5-HT3 receptor antagonists do not modify any aspect of normal behaviour in animals or induce pronounced changes of physiological functions in healthy subjects. Clinical efficacy was shown for various forms of emesis like chemotherapy-induced, radiotherapy-induced, and postoperative emesis, diarrhoea-predominant irritable bowel syndrome, anxiety, chronic fatigue syndrome, alcohol abuse, and in pain syndromes such as fibromyalgia and migraine. Most recent data also suggest that 5-HT3 receptor antagonists are effective for the treatment of other rheumatic diseases such as rheumatoid arthritis, tendinopathies, periarthropathies, and myofascial pain. Other possible indications under discussion are chronic heart pain and bulimia. Unfortunately, experimental findings do not yet provide a homogenous conception of the significance of 5-HT3 receptors in all investigated fields; in nociception, for example, contradictory observations are still inadequately explained and complicated by bell-shaped dose-response curves. Further elucidation and better understanding of the serotonergic neuronal network remains a task for the next decade.
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PMID:Physiology and pathophysiology of the 5-HT3 receptor. 1551 4

Quaternary ammonium derivatives such as cimetropium, n-butyl scopolammonium, otilonium and pinaverium bromide have been discovered and developed as potent spasmolytics of the gastrointestinal tract. Their pharmacological activity has been proven in both "in vivo" and "in vitro" studies of hypermotility. "In vitro" experiments showed that they possess antimuscarinic activity at nM level but only pinaverium and otilonium are endowed with calcium channel blocker properties. These latter compounds relaxed the gastrointestinal smooth muscle mainly through a specific inhibition of calcium ion influx through L-type voltage operated calcium channels. Molecular pharmacology trials have indicated that pinaverium and otilonium can bind specific subunits of the calcium channel in the external surface of the plasma membrane and in this way they block the machinery of the contraction. Recent evidence showed that otilonium is able to bind tachykinin NK(2) receptors and not only inhibits one of the major contractile agents but can reduce the activation of afferent nerves devoted to the passage of sensory signals from the periphery to the central nervous system. Thanks to their typical physico-chemical characteristics, they are poorly absorbed by the systemic circulation and generally remain in the gastrointestinal tract where they exert the muscle relaxant activity by a local activity. Some differences exists in the absorption among these compounds: both n-butyl scopolammonium and cimetropium are partially taken up in the bloodstream, pinaverium has a low absorption (8-10 %) but is endowed with an excellent hepato-biliary excretion and otilonium, which has the lowest absorption (3 %), is almost totally excreted by faeces. Quaternary ammonium derivatives are widely used for the treatment of irritable bowel syndrome and recent meta-analyses have supported their efficacy in this disease. Due to its therapeutic index, the use of n-butyl scopolammonium is more indicated to treat acute colics than a chronic disease such as irritable bowel syndrome. Taking into consideration the published trials carried out with validated methodology in irritable bowel syndrome, cimetropium and otilonium are the best demonstrated drugs for the improvement in global assessment, pain and abdominal distension.
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PMID:Quaternary ammonium derivatives as spasmolytics for irritable bowel syndrome. 1557 53

Irritable bowel syndrome (IBS) is one of several functional gastrointestinal disorders commonly encountered in both the clinical setting and the general population. The biopsychosocial model is currently believed to be a more complete explanatory mechanism of IBS symptom genesis and propagation. Gut inflammation and immune activation is one of the biological mechanisms for which evidence is emerging. Experimental parasitic infection of mice bowel resulted in elevated substance P levels and increased expression of cyclooxygenase 2 (COX 2) enzyme, prostaglandin E2, IL-4, IL-5, and IL-13. In IBS patients, increased cellularity and proximity of the inflammatory or immune cells to the nerve trunks of the bowel, elevated interleukin-1beta mRNA expression in mucosal biopsies, and increased inducible nitric oxide synthase and nitrotyrosine elaboration (indicative of lymphocyte activation) were observed. Corticosteroids given after the elimination of an experimentally applied parasite from the bowel of mice resulted in the reversal of persistent gut muscle dysfunction. Selective COX-2 inhibitors attenuated the increased bowel smooth muscle contractility resulting from parasite infection of mice gut. In humans, it has been observed that the relative risk of developing IBS in asthma patients was reduced by 60% by the use of oral steroids. Despite such preclinical and human evidence for the role of inflammation and immune activation in IBS, the efficacy of anti-inflammatory and immunomodulatory agents has not been adequately investigated. Budesonide, a corticosteroid with a high mucosal activity and a low bioavailability, is an anti-inflammatory agent that may be worth investigating for its utility in diarrhea-predominant IBS.
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PMID:Will corticosteroids and other anti-inflammatory agents be effective for diarrhea-predominant irritable bowel syndrome? 1589 25

The symptomatic management of irritable bowel syndrome (IBS) and functional dyspepsia, which often overlap, can be frustrating and difficult. Education and reassurance remain central for management although controlled trials are lacking. Psychological interventions may be useful in select patients but methodological inadequacies in clinical trials limit their interpretability. For symptom exacerbations, drug treatment is reasonable but no current treatment successfully targets the full symptom complex. Bulking agents are not of proven efficacy in IBS; they may improve constipation but worsen bloating and pain. Anticholinergics are of uncertain value in IBS. A meta-analysis of trials of smooth muscle relaxants for IBS has been reported to be positive but the quality of the trials included was poor. Antidepressants for IBS and functional dyspepsia appear to be efficacious based on the limited published evidence; both global symptoms and abdominal pain improve. Selective serotonin reuptake inhibitors (SSRIs) are of uncertain efficacy but anecdotally appear to be useful. Laxatives are not of proven efficacy in IBS. Loperamide improves diarrhea, but not abdominal pain in IBS. No drug is of proven efficacy for bloating. Acid suppression remains the mainstay of therapy for functional dyspepsia but the majority of patients do not have an adequate response. Promising drugs include new prokinetics for constipation-predominant IBS (e.g., tegaserod, a partial 5-HT4 agonist, prucalopride, a full 5-HT4 agonist, and dexloxiglumide, a cholecystokinin1 antagonist), agents for diarrhea-predominant IBS (e.g., 5-HT3 antagonists, alpha2 receptor agonists and corticotrophin receptor-1 antagonists), other visceral analgesics (e.g. tachykinin antagonists, opioid agonists) and in dyspepsia fundus relaxing agents (e.g., 5-HT1 agonists, tegaserod).
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PMID:New and emerging treatments for irritable bowel syndrome and functional dyspepsia. 1598 38

Fibromyalgia syndrome (FM) is a common chronic pain condition that affects at least 2% of the adult population in the USA and other regions in the world where FM is studied. Prevalence rates in some regions have not been ascertained and may be influenced by differences in cultural norms regarding the definition and attribution of chronic pain states. Chronic, widespread pain is the defining feature of FM, but patients may also exhibit a range of other symptoms, including sleep disturbance, fatigue, irritable bowel syndrome, headache, and mood disorders. Although the etiology of FM is not completely understood, the syndrome is thought to arise from influencing factors such as stress, medical illness, and a variety of pain conditions in some, but not all patients, in conjunction with a variety of neurotransmitter and neuroendocrine disturbances. These include reduced levels of biogenic amines, increased concentrations of excitatory neurotransmitters, including substance P, and dysregulation of the hypothalamic-pituitary-adrenal axis. A unifying hypothesis is that FM results from sensitization of the central nervous system. Establishing diagnosis and evaluating effects of therapy in patients with FM may be difficult because of the multifaceted nature of the syndrome and overlap with other chronically painful conditions. Diagnostic criteria, originally developed for research purposes, have aided our understanding of this patient population in both research and clinical settings, but need further refinement as our knowledge about chronic widespread pain evolves. Outcome measures, borrowed from clinical research in pain, rheumatology, neurology, and psychiatry, are able to distinguish treatment response in specific symptom domains. Further work is necessary to validate these measures in FM. In addition, work is under way to develop composite response criteria, intended to address the multidimensional nature of this syndrome. A range of medical treatments, including antidepressants, opioids, nonsteroidal antiinflammatory drugs, sedatives, muscle relaxants, and antiepileptics, have been used to treat FM. Nonpharmaceutical treatment modalities, including exercise, physical therapy, massage, acupuncture, and cognitive behavioral therapy, can be helpful. Few of these approaches have been demonstrated to have clear-cut benefits in randomized controlled trials. However, there is now increased interest as more effective treatments are developed and our ability to accurately measure effect of treatment has improved. The multifaceted nature of FM suggests that multimodal individualized treatment programs may be necessary to achieve optimal outcomes in patients with this syndrome.
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PMID:Fibromyalgia syndrome: review of clinical presentation, pathogenesis, outcome measures, and treatment. 1607 56

Fibromyalgia (FMS) is a debilitating disorder characterized by chronic diffuse muscle pain, fatigue, sleep disturbance, depression and skin sensitivity. There are no genetic or biochemical markers and patients often present with other comorbid diseases, such as migraines, interstitial cystitis and irritable bowel syndrome. Diagnosis includes the presence of 11/18 trigger points, but many patients with early symptoms might not fit this definition. Pathogenesis is still unknown, but there has been evidence of increased corticotropin-releasing hormone (CRH) and substance P (SP) in the CSF of FMS patients, as well as increased SP, IL-6 and IL-8 in their serum. Increased numbers of activated mast cells were also noted in skin biopsies. The hypothesis is put forward that FMS is a neuro-immunoendocrine disorder where increased release of CRH and SP from neurons in specific muscle sites triggers local mast cells to release proinflammatory and neurosensitizing molecules. There is no curative treatment although low doses of tricyclic antidepressants and the serotonin-3 receptor antagonist tropisetron, are helpful. Recent nutraceutical formulations containing the natural anti-inflammatory and mast cell inhibitory flavonoid quercetin hold promise since they can be used together with other treatment modalities.
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PMID:Fibromyalgia--new concepts of pathogenesis and treatment. 1656 42

Colorectal hyperalgesia has been supposed to be one of the key pathophysiological roles in irritable bowel syndrome (IBS). Recent animal models have demonstrated that neonatal maternal deprivation (stress memory) or repetitive rectal distension (pain memory) in neonatal animal triggers long-term hypersensitivity to rectal distension, indicating that negative events including abuse or maternal separation in childhood may play a crucial role on development of IBS. Several molecules such as corticotropin-releasing factor, serotonin, nerve growth factor, myosin light chain kinase, chemical mediators from mast cell, substance P and calcitonin gene-related peptide released from transient receptor potential vanilloid receptor 1 (TRPV1)-positive primary afferent nerves have been proved to induce visceral hyperalgesia. Novel drugs based on these findings have been developed.
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PMID:[Visceral hypersensitivity]. 1689 10


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