Authors: Burton MB, Gebhart GF.

Institution: Department of Pharmacology, University of Iowa, Iowa City 52242, USA.

Summary: The present study was undertaken to examine the effects of chemical irritation of the colon on responses to noxious colorectal distension (CRD) in the rat. Pressor and abdominal visceromotor (electromyographic, EMG) responses to CRD were examined in chronically instrumented, unanesthetized rats before and at 6 and 24 h after intracolonic instillation of 5% acetic acid (HAc) or saline.

The magnitude of the visceromotor response to phasic CRD (80 mmHg, 20 s) was significantly greater in HAc- than in saline-treated rats at both 6 and 24 h. This was accompanied by a significant increase in the resting EMG activity in both groups, but not between groups. There was, however, no change produced in either the resting mean arterial pressure (MAP) or the magnitude of the pressor response to CRD by HAc treatment.

Signs of colonic inflammation (leukocyte infiltration) were examined periodically after HAc treatment, but were apparent only at 24 h. It is concluded that mechanical (distension) and chemical irritation (HAc) of the colon can elicit changes in the basal visceromotor activity and the visceromotor response to CRD. These changes seem to reflect an alteration in the sensitivity of the colon to noxious stimuli.

Study link: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7749755&query_hl=12&itool=pubmed_DocSum

Authors: Gschossmann JM, Adam B, Liebregts T, Buenger L, Ruwe M, Gerken G, Mayer EA, Holtmann G.

Institution: Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Essen, Hufelandstrasse 55, 45122 Essen, Germany.

Background: Acute mucosal inflammation may initiate alterations of visceral sensory function. However, experimental studies on the potential effects of a transient inflammation on visceral sensitivity are lacking.

Results: TNB/ethanol but not saline induced an acute colitis, with most severe histological lesions occurring 5 days after instillation. After 14 days, there was no histological evidence for persisting mucosal alterations. Five days after induction of TNB/ethanol colitis, the VMR to CRD reached a transient increase (P < 0.05 v. baseline), which returned to baseline levels by day 14. In control experiments (rectal saline instillation), the VMR to CRD decreased significantly compared with baseline values (P < 0.05).

Conclusion: Following an acute colitis due to single colorectal instillation of TNB/ethanol, histological changes are associated with an enhanced nociceptive response to CRD.

Link study: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12362096&query_hl=12&itool=pubmed_DocSum

Authors: Jacobson K, McHugh K, Collins SM.

Institution: Department of Medicine, McMaster University Medical Center, Hamilton, Ontario, Canada.

Background: Studies in inflammatory bowel disease have shown extensive structural abnormalities in the enteric nervous system of inflamed and noninflamed gut; however, functional correlates are lacking. The aim of this study was to determine the effect of colitis on myenteric nerve function at inflamed and noninflamed sites in rat intestine.

Methods: Tritiated noradrenaline release was measured from longitudinal muscle myenteric plexus preparations from the distal and transverse colon and terminal ileum of rats with colitis induced by trinitrobenzene sulfonic acid or Trichinella spiralis larvae.

Conclusions: Experimental distal colitis alters myenteric nerve function in inflamed distal colon and noninflamed gut regions. These changes are independent of the manner in which colitis is induced and provide a basis for the extensive disruption of physiological function observed in inflammatory bowel disease.

Study link: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7657099&query_hl=21&itool=pubmed_docsum

Authors: Sanovic S, Lamb DP, Blennerhassett MG.

Institution: Gastrointestinal Diseases Research Unit, Queens University, Hotel Dieu Hospital, Kingston, Ontario, Canada.

Summary: Inflammation of the intestine causes pain and altered motility, at least in part through effects on the enteric nervous system. While these changes may be reversed with healing, permanent damage may contribute to inflammatory bowel disease (IBD) and post-enteritis irritable bowel syndrome.

Since little information exists, we induced colitis in male Sprague-Dawley rats with dinitrobenzene sulfonic acid and used immunocytochemistry to examine the number and distribution of enteric neurons at times up to 35 days later. Inflammation caused significant neuronal loss in the inflamed region by 24 hours, with only 49% of neurons remaining by days 4 to 6 and thereafter, when inflammation had subsided.

Eosinophils were found within the myenteric plexus at only at the earliest time points, despite a general infiltration of neutrophils into the muscle wall. While the number of myenteric ganglia remained constant, there was significant decrease in the number of ganglia in the submucosal plexus. Despite reduced neuronal number and hyperplasia of smooth muscle, the density of axons among the smooth muscle cells remained unchanged during and after inflammation.

Intracolonic application of the topical steroid budesonide caused a dose-dependent prevention of neuronal loss, suggesting that evaluation of anti-inflammatory therapy in inflammatory bowel disease should include quantitative assessment of neural components.

Study link: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10514387&query_hl=12&itool=pubmed_docsum

Authors: Collins SM, McHugh K, Jacobson K, Khan I, Riddell R, Murase K, Weingarten HP.

Institution: Intestinal Diseases Research Unit, McMaster University, Hamilton, Ontario, Canada.

Background & Aims: Patients with inflammatory bowel disease have symptoms of irritable bowel syndrome (IBS) with a higher than expected prevalence. Stress is an important factor in the pathogenesis of IBS. Thus, previous inflammation may predispose to IBS by rendering the bowel more susceptible to the impact of stress. The aim of this study was to examine the effect of previous colitis on stress-induced responses in rats.

Methods: Acute colitis was induced in rats by intrarectal administration of trinitrobenzene sulfonic acid (TNBS), and the rats were allowed to recover for 6 weeks before application of mild restraint stress for 3 consecutive days. In vitro measurements included myeloperoxidase activity, plasma corticosterone levels, interleukin 1 beta messenger RNA expression, and [3H]noradrenaline release from the myenteric plexus.

Results: Six weeks after administration of TNBS, stress caused a significant increase in myeloperoxidase activity in TNBS-treated rats but not in stressed controls; plasma corticosterone responses were similar. Stress also caused an exaggerated and significant suppression of [3H]noradrenaline release in TNBS-treated stressed rats compared with stressed controls. This was accompanied by a significant decrease in interleukin 1 beta messenger RNA expression in the colon.

Conclusion: Previous colitis rendered the colon more susceptible to effects of stress on enteric nerve function and also increased some parameters of inflammation in response to stress.

Study link: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8942729&query_hl=12&itool=pubmed_docsum

Authors: La JH, Kim TW, Sung TS, Kim HJ, Kim JY, Yang IS.

Institution: Department of Physiology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.

Aim: Irritable bowel syndrome (IBS) is a functional bowel disorder. Its major symptom is bowel dysmotility, yet the mechanism of the symptom is poorly understood. Since the neurokinin-1 receptor (NK1R)-mediated signaling in the gut is important in the control of normal bowel motor function, we aimed to investigate whether the NK1R-mediated bowel motor function was altered in IBS, using a rat IBS model that was previously reported to show colonic dysmotility in response to restraint stress.

Methods: IBS symptoms were produced in male Sprague-Dawley rats by inducing colitis with acetic acid. Rats were left to recover from colitis for 6 d, and used for experiments 7 d post-induction of colitis. Motor activities of distal colon were recorded in vitro.

Conclusion: These results suggest that the NK1R-meidated colonic motor response is increased in IBS rats, due to the decrease in the nitrergic inhibitory neural component.

Study link: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15633223&query_hl=12&itool=pubmed_docsum

Authors: La JH, Kim TW, Sung TS, Kim HJ, Kim JY, Yang IS.

Institution: Department of Physiology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea.

Summary: The involvement of mucosal mast cells (MMC) in the pathophysiology of irritable bowel syndrome (IBS) is still controversial. We aimed to re-evaluate the role of MMC in visceral hypersensitivity associated with IBS using a rat IBS model that develops the IBS symptom after a subsidence of acetic acid-induced colitis. No significant difference in the number of MMC was observed between normal rat colon and IBS rat colon. (61.7 +/- 2.9/mm(2) in normal vs. 88.7 +/- 13.3/mm(2) in IBS, p > 0.29).

However, the degranulation rate of MMC was significantly higher in IBS rat colon (49.5 +/- 2.4% in normal vs. 68.8 +/- 3.4% in IBS, p < 0.05). Pretreatment of a mast cell stabilizer, doxantrazole (5 mg/kg, i.p.), reduced the degranulation rate of MMC and significantly attenuated visceral hypersensitivity to rectal distension in IBS rat, whereas it had no effect on the visceral sensory responses in normal rat. These results suggest that, although the number of MMC is not significantly changed in IBS rat colon, the higher degranulation rate of MMC is responsible for visceral hypersensitivity in this model IBS.

Study link: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15613815&query_hl=12&itool=pubmed_docsum

Authors: Hosseini JM, Goldhill JM, Bossone C, Pineiro-Carrero V, Shea-Donohue T.

Institution: Department of Physiology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4799, USA.

Summary: The present study was designed to investigate inflammation-induced changes in smooth muscle responses to acetylcholine and the tachykinins that may contribute to the abnormal motility associated with inflammatory bowel disease.

Colitis was induced in male Sprague-Dawley rats by intrarectal administration of trinitrobenzenesulphonic acid in ethanol. After either 4 h (acute) or 7 days (chronic) the distal colon was taken for in vitro measurement of smooth muscle tension and histological assessment. Acute colitis featured injury and neutrophilic infiltration confined to the mucosa while chronic inflammation showed marked injury, lymphocytic infiltration and muscle thickening.

Acute inflammation increased responses to substance P and acetylcholine but decreased responses to neurokinin A. The enhanced response to substance P was dependent on nerves, while the decreased response to neurokinin A reflected a reduction in activity at the level of the smooth muscle. In the saline group, there was evidence of cholinergic interaction with substance P, but not neurokinin A.

Substance P modulation of cholinergic nerves was absent in acute inflammation. Responses to all neurotransmitters were decreased in the chronic stage. These data demonstrate progressive changes in the smooth muscle function during acute and chronic colitis that may contribute to the abnormal motility associated with inflammatory bowel disease.

Study link: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10520166&query_hl=13&itool=pubmed_docsum

Authors: Kimball ES, Palmer JM, D'Andrea MR, Hornby PJ, Wade PR.

Institution: Enterology Research Team, Johnson and Johnson Pharmaceutical, Research and Development, Welsh and McKean Roads, PO Box 776, Spring House, PA, 19477-0776, USA. ekimball@prdus.jnj.com

Summary: Oil of mustard (OM) is a potent neuronal activator that promotes allodynia and hyperalgesia within minutes of application. In this study, OM was used to induce an acute colitis. We also investigated whether intracolonic OM-induced inflammation alters gastrointestinal (GI) function over a longer time frame as a model of postinflammatory irritable bowel syndrome (PI-IBS).

Mice given a single administration of 0.5% OM developed a severe colitis that peaked at day 3, was reduced at day 7, and was absent by day 14. At the peak response, there was body weight loss, colon shrinkage, thickening and weight increases, distension of the proximal colon, and diarrhea. Macroscopic inspection of the distal colon revealed a discontinuous pattern of inflammatory damage and occasional transmural ulceration. Histological examination showed loss of epithelium, an inflammatory infiltrate, destruction of mucosal architecture, edema, and loss of circular smooth muscle architecture.

OM administration increased transit of a carmine dye bolus from 58% of the total length of the upper GI tract in untreated age-matched controls to as high as 74% when tested at day 28 post-OM. Mice in the latter group demonstrated a significantly more sensitive response to inhibition of upper GI transit by the mu-opioid receptor agonist loperamide compared with normal mice.

OM induces a rapid, acute, and transient colitis and, in the longer term, functional changes in motility that are observed when there is no gross inflammation and thereby is a model of functional bowel disorders that mimic aspects of PI-IBS in humans.

Study link: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15691868&query_hl=7&itool=pubmed_docsum

Authors: La JH, Kim TW, Sung TS, Kang JW, Kim HJ, Yang IS.

Institution: Department of Physiology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.

Aim: Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by visceral hypersensitivity and altered bowel motility. There is increasing evidence suggesting the role of inflammation in the pathogenesis of IBS, which addresses the possibility that formerly established rat model of colitis could be used as an IBS model after the inflammation subsided.

Methods: Colitis was induced by intracolonic instillation of 4% acetic acid in male Sprague-Dawley rats. The extent of inflammation was assessed by histological examination and myeloperoxidase (MPO) activity assay. After subsidence of colitis, the rats were subjected to rectal distension and restraint stress, then the abdominal withdrawal reflex and the number of stress-induced fecal output were measured, respectively.

Results: At 2 days post-induction of colitis, the colon showed characteristic inflammatory changes in histology and 8-fold increase in MPO activity. At 7 days post-induction of colitis, the histological features and MPO activity returned to normal. The rats at 7 days post-induction of colitis showed hypersensitive response to rectal distension without an accompanying change in rectal compliance, and defecated more stools than control animals when under stress.

Conclusion: These results concur largely with the characteristic features of IBS, visceral hypersensitivity and altered defecation pattern in the absence of detectable disease, suggesting that this animal model is a methodologically convenient and useful model for studying a subset of IBS.

Study link: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14669335&query_hl=149

Authors: Grossi L, McHugh K, Collins SM.

Institution: Intestinal Diseases Research Unit, McMaster University, Hamilton, Ontario, Canada.

Background: Studies on muscle contraction in colitis yield conflicting data that may reflect differences in the manner in which colitis is induced. Therefore, we compared distal colonic longitudinal muscle contraction in four models of colitis in the rat.

Method: Distal colitis was induced by intrarectal administration of trinitrobenzene sulfonic, acetic acid, or Trichinella spiralis larvae, or by intraperitoneal injection of mitomycin C. Colonic myeloperoxidase activity was used to monitor acute inflammation. RESULTS: Myeloperoxidase activity increased in each model of colitis. In trinitrobenzene-treated rats, contractile responses to carbachol, substance P, and KCl decreased by 64%, 76%, and 58%, respectively. In acetic acid treated rats, responses induced by carbachol, substance P, or KCl were each significantly decreased by 73%, 68%, and 55% and were similarly reduced by 42%, 77%, and 46%, respectively, in rats with T. spiralis colitis. In mitomycin-induced colitis, these respective responses also decreased significantly by 71%, 55%, and 54%.

Conclusion: Decreased contractility of longitudinal muscle in acute colitis in rats is independent of the manner in which the colitis is induced and is mediated at a receptor-independent locus on the muscle cell.

Study link: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8462793&query_hl=133