Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022104 (irritable bowel syndrome)
 8,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In recent times, the perception of functional gastrointestinal disorders such as irritable bowel syndrome (IBS) has shifted fundamentally. Such disorders are now thought of as serious diseases characterized by perturbations in the neuronal regulation of gastrointestinal function. The concept of visceral hypersensitivity, the characterization of neuronal networks in the 'brain-gut axis' and the identification of several novel 5-HT-mediated mechanisms have contributed to this shift. Here, we review how some of the more promising of these new mechanisms (e.g. those involving 5-HT transporters and the 5-HT(2B), 5-HT(7) and putative 5-HT(1p) receptors) might lead to a range of second-generation therapies that could revolutionize the treatment of functional gastrointestinal disorders, particularly IBS.
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PMID:5-HT in the enteric nervous system: gut function and neuropharmacology. 1712 21

Recent studies have shown that mucosal serotonin (5-HT) transporter (SERT) expression is decreased in animal models of colitis, as well as in the colonic mucosa of humans with ulcerative colitis and irritable bowel syndrome. Altered SERT function or expression may underlie the altered motility, secretion, and sensation seen in these inflammatory gut disorders. In an effort to elucidate possible mediators of SERT downregulation, we treated cultured colonic epithelial cells (Caco2) with conditioned medium from activated human lymphocytes. Application of the conditioned medium caused a decrease in fluoxetine-sensitive [(3)H]5-HT uptake. Individual proinflammatory agents were then tested for their ability to affect uptake. Cells were treated for 48 or 72 h with PGE(2) (10 microM), IFN-gamma (500 ng/ml), TNF-alpha (50 ng/ml), IL-12 (50 ng/ml), or the nitric oxide-releasing agent S-nitrosoglutathione (GSNO; 100 microM). [(3)H]5-HT uptake was then measured. Neither PGE nor IL-12 had any effect on [(3)H]5-HT uptake, and GSNO increased uptake. However, after 3-day incubation, both TNF-alpha and IFN-gamma elicited significant decreases in SERT function. Neither TNF-alpha nor IFN-gamma were cytotoxic when used for this period of time and at these concentrations. These two cytokines also induced decreases in SERT mRNA and protein levels. By altering SERT expression, TNF-alpha and IFN-gamma could contribute to the altered motility and expression seen in vivo in ulcerative colitis or irritable bowel syndrome.
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PMID:IFN-gamma and TNF-alpha decrease serotonin transporter function and expression in Caco2 cells. 1717 25

Serotonin (5-HT) is most commonly thought of as a neurotransmitter in the central nervous system. However, the predominant site of serotonin synthesis, storage, and release is the enterochromaffin cells of the intestinal mucosa. Within the intestinal mucosa, serotonin released from EC cells activates neural reflexes associated with intestinal secretion, motility, and sensation. Two important receptors for serotonin that are located in the neural circuitry of the intestines are the 5-HT(3) and 5-HT(4) receptors; these are the targets of drugs designed to treat gastrointestinal disorders. 5-HT(3) receptor antagonists are used to treat nausea and emesis associated with chemotherapy and for functional disorders associated with diarrhea. 5-HT(4) receptor agonists are used as promotility agents to promote gastric emptying and to alleviate constipation. Because of the importance of serotonin in normal gut function and sensation, a number of studies have investigated potential changes in mucosal serotonin signaling in pathologic conditions. Despite the inconsistencies in the current literature, changes in serotonin signaling have now been demonstrated in inflammatory bowel disease, irritable bowel syndrome, postinfectious irritable bowel syndrome, and idiopathic constipation. Emerging evidence has led to many contradictory theories regarding serotonin signaling and its roles in the pathology of gut disorders. This review summarizes the current medications affecting serotonin signaling and provides an overview of our current knowledge of the changes in serotonin that occur in pathologic conditions.
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PMID:Serotonin and its role in colonic function and in gastrointestinal disorders. 1719 2

1. 5-Hydroxytryptamine (5-HT) has an important role in the pathogenesis of irritable bowel syndrome. To investigate the effects of 5-HT on the contractile activity of myocytes of the guinea-pig proximal colon, cell imaging before and after contraction was undertaken and images were analysed using image-analysis software. Ion currents and membrane potentials were measured. Cytoplasmic free Ca(2+) was recorded using a confocal microscope following loading of the cells with the fluorescent probe Fura-2AM. 2. 5-Hydroxytryptamine reduced cell length in a dose-dependent manner (EC(50) = 0.189 micromol/L). Under current clamp, 10 micromol/L 5-HT reduced action potential amplitude (measured as peak height) and decreased action potential duration, as well as depolarizing the resting potential from -68.4 +/- 3.6 to -22.96 +/- 4.65 mV. Iberiotoxin (1 micromol/L) blocked the effects of 5-HT in reducing the time to repolarization (T(90)) and nicardipine (5 micromol/L) blocked the effects of 5-HT in reducing action potential amplitude. 3. In the whole-cell mode, 5-HT enhanced L-type Ca(2+) currents, large conductance K(+) channel (BK(Ca)) currents and spontaneous transient outward currents (STOC). In addition, 5-HT increased intracellular Ca(2+) levels. Ondansetron (10 micromol/L) blocked the effects of 5-HT in enhancing L-type Ca(2+) currents, BK(Ca) currents and STOC. 4. In conclusion, 5-HT induces contraction of colonic myocytes, mostly as a result of Ca(2+) release from the sarcoplasmic reticulum (SR) following activation of 5-HT(3) receptors and the inositol 1,4,5-trisphosphate pathway. In addition, the effect of 5-HT in decreasing action potential amplitude is mediated by the release of Ca(2+) from the SR, as well as by enhanced L-type Ca(2+) current. 5-Hydroxytryptamine decreased action potential duration by enhancing BK(Ca) current.
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PMID:Mechanisms mediating serotonin-induced contraction of colonic myocytes. 1720 46

Serotonin is an important gastrointestinal signaling molecule. It is a paracrine messenger utilized by enterochromaffin (EC) cells, which function as sensory transducers. Serotonin activates intrinsic and extrinsic primary afferent neurons to, respectively, initiate peristaltic and secretory reflexes and to transmit information to the central nervous system. Serotonin is also a neurotransmitter utilized by a system of long descending myenteric interneurons. Serotonin is synthesized through the actions of 2 different tryptophan hydroxylases, TpH1 and TpH2, which are found, respectively, in EC cells and neurons. Serotonin is inactivated by the serotonin reuptake transporter (SERT)-mediated uptake into enterocytes or neurons. The presence of many serotonin receptor subtypes enables selective drugs to be designed to therapeutically modulate gastrointestinal motility, secretion, and sensation. Current examples include tegaserod, a 5-HT(4) partial agonist, which has been approved for treatment of irritable bowel syndrome (IBS) with constipation in women and for chronic constipation in men and women. The 5-HT(3) antagonists, granisetron and ondansetron, are useful in combating the nausea associated with cancer chemotherapy, and alosetron is employed in the treatment of IBS with diarrhea. Serotonergic signaling abnormalities have also been putatively implicated in the pathogenesis of functional bowel diseases. Other compounds, for which efficacy has not been rigorously established, but which may have value, include tricyclic antidepressants and serotonin selective reuptake inhibitors to combat IBS, and 5-HT(1) agonists, which enhance gastric accommodation, to treat functional dyspepsia. The initial success encountered with serotonergic agents holds promise for newer and more potent insights and therapies of brain-gut disorders.
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PMID:The serotonin signaling system: from basic understanding to drug development for functional GI disorders. 1724 88

5-HT(3) antagonists are effective treatments for chemotherapy-induced emesis and diarrhoea and urgency and pain associated with irritable bowel syndrome. Reports of ischaemic colitis led to restricted use of the approved drug, alosetron. This article briefly reviews the controversial information from epidemiology and adverse reaction reports and addresses the experimental basis for the development of ischaemic colitis as a result of 5-HT(3) antagonist treatment. The author reviews the potential factors based involved in the ischaemic colitis and ways in which this class of compound may influence those factors based on experimental evidence, including the literature on any vascular effects of these agents. Finally, the article addresses the theoretical basis for the constipation as a predisposing factor for the development of ischaemic colitis. The evidence reviewed suggests that further studies are needed to explore the principles to prove or disprove the association.
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PMID:Is there an experimental basis for the development of ischaemic colitis as a result of 5-HT3 antagonist treatment? 1724 61

Tegaserod, a selective and partial agonist at the 5-hydroxytryptamine (5-HT [serotonin]) receptor subtype 4 (5-HT4), is the only United States Food and Drug Administration-approved drug for the treatment of constipation-predominant irritable bowel syndrome (IBS) in women. The drug's stimulation of 5-HT4 receptors on intestinal enterocytes increases peristaltic activity and fluid secretion into the gut lumen, facilitating stool passage. In addition, affinity of tegaserod for 5-HT4 receptors modulates visceral sensitivity, which helps alleviate abdominal pain associated with constipation-predominant IBS. The drug's pharmacokinetic and pharmacodynamic parameters do not differ significantly with age or sex. Tegaserod safely and effectively relieves overall gastrointestinal symptoms and abdominal discomfort and normalizes bowel habits in patients with constipation-predominant IBS. It is associated with few drug interactions. In clinical studies, tegaserod was well tolerated, and its adverse-effect profile was similar to that of placebo. Severe diarrhea, as well as abdominal pain, flatulence, headache, and nausea, were the most commonly reported events. Patients who experience severe diarrhea should discontinue the drug. With the data available, tegaserod remains an option for patients with constipation-predominant IBS.
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PMID:Tegaserod for constipation-predominant irritable bowel syndrome. 1725 16

The 5-HT3 receptor is a pentameric ligand-gated cation channel which is found in the central and peripheral nervous system and on extraneuronal locations like lymphocytes, monocytes and fetal tissue. Five monomer subtypes, the 5-HT(3A-E) subunits, have been identified which show differences in the amino-terminal and the transmembrane region. The functional relevance of different receptor compositions is not yet clarified. 5-HT3 receptors are located predominantly in CNS regions that are involved in the integration of the vomiting reflex, pain processing, the reward system and anxiety control. The preferential localization on nerve endings is consistent with a physiological role of 5-HT3 receptors in the control of neurotransmitter release such as dopamine, cholecystokinin, glutamate, acetylcholine, GABA, substance P, or serotonin itself. 5-HT3-receptor agonists cause unpleasant effects like nausea and anxiety, and no clinical use has been considered. In contrast, the introduction of 5-HT3-receptor antagonists for chemotherapy-induced vomiting was extremely successful. After development of other gastrointestinal indications like postoperative vomiting and diarrhea-predominant irritable bowel syndrome recent research focuses on rheumatological indications such as fibromyalgia, rheumatoid arthritis and tendinopathies. Positive effects have also been observed for pain syndromes such as chronic neuropathic pain and migraine. These effects seem to be related to substance P-mediated inflammation and hyperalgesia. Furthermore, antiinflammatory and immunomodulatory properties have been observed for 5-HT3-receptor antagonists which might explain promising findings in systemic sclerosis and other immunological conditions. For all of these innovative indications the optimal dosing schedule is a crucial issue, since a bell-shaped dose-response curve has been observed repeatedly for 5-HT3-receptor antagonists, particularly in CNS effects.
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PMID:The neuronal 5-HT3 receptor network after 20 years of research--evolving concepts in management of pain and inflammation. 1731 6

Ramosetron is a potent and selective serotonin (5-HT)(3) receptor antagonist that has been shown to affect abnormal colonic function and abdominal pain in animals. Ramosetron (0.3 to 100 microg/kg, p.o.) has been found to significantly suppress abnormal defecation induced by conditioned-fear stress (CFS), restraint stress, corticotropin releasing factor (CRF) and 5-HT in rats and mice, and these effects were more potent than those of alosetron, cilansetron or loperamide. On the other hand, ramosetron (3,000 microg/kg, p. o., once daily for 7 days) did not inhibit normal defecation in dogs while tiquizium significantly inhibited it. Ramosetron (3 to 100 microg/kg, p. o.) also significantly prevented CFS-induced acceleration of colonic transit and CRF-induced abnormal water transport in rats, respectively. Moreover, ramosetron (0.3 to 3 microg/kg, p. o.) significantly suppressed restraint stress-induced decrease in colonic pain threshold, an effect not observed with loperamide. These results indicate that ramosetron produce beneficial clinical effects on IBS symptoms.
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PMID:Pharmacological profile of ramosetron, a novel therapeutic agent for IBS. 1732 87

In the gut, 5-HT acts as a paracrine signalling molecule released by enterochromaffin cells and as a transmitter released by some descending serotonergic interneurons. It has a prominent role in the regulation of motility, vascular tone, secretion and perception both in normal and under certain pathophysiological conditions, such as the carcinoid syndrome and the irritable bowel syndrome (IBS). Serotonin is known to markedly influence bowel function by activating at least five receptor types (5-HT(1,2,3,4,7)). Among all 5-HT receptors, those belonging to the 5-HT3 (a ionotropic receptor) and 5-HT4 (a metabotropic receptor) type are the most extensively studied in gastroenterology, resulting in commercially available (although not worldwide) serotonergic agents for the treatment of IBS and functional dyspepsia. Recently, 5-HT7 receptors have been found to participate in the accommodation process of the circular muscle during the preparatory phase of ileal peristalsis. Since an exaggerated accommodation of the gut wall may contribute to abdominal distension and bloating, 5-HT7 receptor ligands may offer innovative opportunities for the pharmacological treatment of functional bowel disorders.
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PMID:[Recent insights into the pathogenesis of abdominal symptoms in functional bowel disorders]. 1743 64


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