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      Upregulation of the high-affinity choline transporter in colon relieves stress-induced hyperalgesia

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          Irritable bowel syndrome (IBS) is a common disease with hyperalgesia, the mechanisms of which remain elusive. The cholinergic system is known to be involved in pain inhibitory pathways in multiple diseases, and its involvement in IBS is unknown.


          We aimed to determine whether high-affinity choline transporter CHT1, a major determinant of the cholinergic signaling capacity, is involved in regulating intestinal sensations associated with stress-induced visceral pain.

          Materials and methods

          An IBS rat model was established by chronic water avoidance stress (WAS). Colonic pathologic alterations were detected by H&E staining. Visceral sensations were determined by scoring the abdominal withdrawal reflex (AWR) and visceromotor response (VMR) magnitude of the electromyogram in response to colorectal distension (CRD). Abdominal mechanical hyperalgesia was assessed by counting the number of withdrawal events evoked by applying von Frey filaments. Real-time PCR, Western blot, and immunostaining were performed to identify CHT1 expression in the colon. Acetylcholine (ACh) secretion was determined by ELISA. Effects of MKC-231, a choline uptake enhancer, on visceral pain were examined.


          After 10 days of WAS exposure, AWR score and VMR magnitude in response to CRD were significantly enhanced and the number of withdrawal events was elevated. Protein and mRNA levels of CHT1 were considerably increased in the colon after WAS. CHT1 upregulation in the WAS-exposed group was largely abolished by ammonium pyrrolidinedithiocarbamate. The density of CHT1-positive intramuscular cells and enteric neurons in the myenteric plexus was enhanced in WAS-exposed rats. Pharmacologic enhancement of CHT1 activity by MKC-231 gavage could relieve the visceral pain of WAS rats by upregulating CHT1 protein expression and enhancing ACh production.


          CHT1 may exert an antinociceptive effect in stress-induced visceral pain by modulating ACh synthesis through nuclear factor kappa B signaling. MKC-231 could be used as a potential drug to treat disorders with hyperalgesia.

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          Most cited references 43

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          Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis.

          Many cross-sectional surveys have reported the prevalence of irritable bowel syndrome (IBS), but there have been no recent systematic review of data from all studies to determine its global prevalence and risk factors. MEDLINE, EMBASE, and EMBASE Classic were searched (until October 2011) to identify population-based studies that reported the prevalence of IBS in adults (≥15 years old); IBS was defined by using specific symptom-based criteria or questionnaires. The prevalence of IBS was extracted for all studies and based on the criteria used to define it. Pooled prevalence, according to study location and certain other characteristics, odds ratios (ORs), and 95% confidence intervals (CIs) were calculated. Of the 390 citations evaluated, 81 reported the prevalence of IBS in 80 separate study populations containing 260,960 subjects. Pooled prevalence in all studies was 11.2% (95% CI, 9.8%-12.8%). The prevalence varied according to country (from 1.1% to 45.0%) and criteria used to define IBS. The greatest prevalence values were calculated when ≥3 Manning criteria were used (14%; 95% CI, 10.0%-17.0%); by using the Rome I and Rome II criteria, prevalence values were 8.8% (95% CI, 6.8%-11.2%) and 9.4% (95% CI, 7.8%-11.1%), respectively. The prevalence was higher for women than men (OR, 1.67; 95% CI, 1.53-1.82) and lower for individuals older than 50 years, compared with those younger than 50 (OR, 0.75; 95% CI, 0.62-0.92). There was no effect of socioeconomic status, but only 4 studies reported these data. The prevalence of IBS varies among countries, as well as criteria used to define its presence. Women are at slightly higher risk for IBS than men. The effects of socioeconomic status have not been well described. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.
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            Activation of the mucosal immune system in irritable bowel syndrome.

            A role for the mucosal immune system in the pathogenesis of irritable bowel syndrome is suggested by its association with intestinal infections. To investigate this, we performed histologic and immunohistologic studies on colonoscopic biopsy specimens from 77 patients with symptoms satisfying the Rome criteria and 28 asymptomatic control patients. Histologic assessment of biopsy specimens from symptomatic patients indicated 3 different groups. The first (38 of 77) had normal conventional histology; however, immunohistology showed increased intraepithelial lymphocytes (median, 1.8-fold; range, 1.74-1.86), lamina propria CD3(+) cells (2-fold; range, 1.55-2.91), and CD25(+) cells (6.5-fold; range, 4.98-8.13) compared with asymptomatic controls. The second group (31 of 77) had nonspecific microscopic inflammation and on immunohistology showed similar increases in lymphocyte populations (not significant vs. the uninflamed group) as well as increased numbers of neutrophil leukocytes and mast cells (P < 0.0001 vs. controls and the uninflamed group). The third group (8 of 77) fulfilled histologic and immunohistologic criteria for classic lymphocytic colitis. Examination of colonoscopic biopsy specimens from patients meeting the Rome criteria for a clinical diagnosis of irritable bowel syndrome showed subgroups with normal and abnormal conventional histology. All groups showed increased numbers of activated immunocompetent cells in the intestinal mucosa on quantitative immunohistology, implicating the mucosal immune system in pathogenesis.
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              A new model of chronic visceral hypersensitivity in adult rats induced by colon irritation during postnatal development.

              The irritable bowel syndrome (IBS) is a common disorder characterized by abdominal pain in the setting of altered perception of viscerosensory stimuli. This so-called visceral hyperalgesia occurs in the absence of detectable organic disease in the peripheral organs and may cause normal or physiologic contractions to be perceived as painful. Although the pathogenesis of IBS remains speculative and is probably multifactorial, a prevailing paradigm is that transient noxious events lead to long-lasting sensitization of the neural pain circuit, despite complete resolution of the initiating event. Neonatal male Sprague-Dawley rats received either mechanical or chemical colonic irritation between postnatal days 8 and 21 and were tested when they became adults. The abdominal withdrawal reflex and the responses of viscerosensitive neurons were recorded during colon distention. Colon irritation in neonates, but not in adults, results in chronic visceral hypersensitivity, with characteristics of allodynia and hyperalgesia, associated with central neuronal sensitization in the absence of identifiable peripheral pathology. These results concur largely with observations in patients with IBS, providing a new animal model to study IBS and validating a neurogenic component of functional abdominal pain that encourages novel approaches to health care and research.

                Author and article information

                J Pain Res
                J Pain Res
                Journal of Pain Research
                Journal of Pain Research
                Dove Medical Press
                21 September 2018
                : 11
                : 1971-1982
                [1 ]Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China, yubp62@ 123456163.com
                [2 ]Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei, China, yubp62@ 123456163.com
                Author notes
                Correspondence: Bao-Ping Yu, Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 238 Jiefang Rd, Wuhan 430060, Hubei, China, Tel +86 276 875 9391, Email yubp62@ 123456163.com
                © 2018 Lin and Yu. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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