Behavioral and molecular processing of visceral pain in the brain of mice: impact of colitis and psychological stress (original) (raw)
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Experimental colitis alters myenteric nerve function at inflamed and noninflamed sites in the rat
Gastroenterology, 1995
Background & Aims: 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. Results: As characterized by myeloperoxidase activity and histology, both models induced inflammation restricted to the distal colon. In the distal colon in trinitrobenzene sulfonic acid colitis, KCI-or electrical field stimulation-evoked 3H release was suppressed by 56% and 60%, respectively; in T. spiralis-infected rats, the KCI-evoked release was suppressed by 58%. 3H release was also suppressed by similar magnitudes in noninflamed transverse colon and terminal ileum of each model. 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.
Post-inflammatory modification of colonic afferent mechanosensitivity
Clinical and Experimental Pharmacology and Physiology, 2009
1. The present review discusses interactions between the immune and nervous systems in post-infectious irritable bowel syndrome (PI-IBS). 2. Visceral pain is the single symptom that most affects the quality of life of patients with irritable bowel syndrome (IBS), yet it is the least successfully managed. An underlying hypersensitivity of colonic afferents to mechanical stimuli has long been implicated in visceral pain in IBS, but little more is known of the physiological aetiology. 3. The PI-IBS patients are a cohort of IBS patients who attribute their symptoms to a preceding gastrointestinal infection by pathogens such as Campylobacter or Salmonella. Current evidence suggests that the immune system remains activated in these patients and contributes to their visceral hypersensitivity. This is characterized by a shift in the phenotype of circulating immune cells towards a Type 1 (Th1 predominating) state. Products from these immune cells sensitize colonic afferents to mechanical stimuli. 4. Rectal instillation of trinitrobenzene sulphonic acid induces a Th1-mediated inflammatory response, consistent with clinical observations in PI-IBS. The visceral hypersensitivity observed in this model is biphasic, with an initial onset characterized by visceral hypersensitivity correlating with histological damage followed by a delayed phase that occurs after histological recovery. Interestingly, this chronic visceral hypersensitivity is mediated by afferents in closest apposition to blood vessels, but furthest from the initial site of damage. 5. Both clinical and experimental evidence indicates that chronic dysregulation of the immune system induces visceral afferent hypersensitivity and, therefore, may be the central mechanism underlying PI-IBS.
2015
Objectives Experiments using P2X 3 knockout mice or more general P2X receptor antagonists suggest that P2X 3 receptors contribute to visceral hypersensitivity. We aimed to investigate the effect of the selective P2X 3 antagonist A-317491 on visceral sensitivity under physiological conditions, during acute colitis and in the post-inflammatory phase of colitis. Methods Trinitrobenzene sulphonic-acid colitis was monitored by colonoscopy: on day 3 to confirm the presence of colitis and then every 4 days, starting from day 10, to monitor convalescence and determine the exact timepoint of endoscopic healing in each rat. Visceral sensitivity was assessed by quantifying visceromotor responses to colorectal distension in controls, rats with acute colitis and post-colitis rats. A-317491 was administered 30 min prior to visceral sensitivity testing. Expression of P2X 3 receptors (RT-PCR and immunohistochemistry) and the intracellular signalling molecules cdk5, csk and CASK (RT-PCR) were quantified in colonic tissue and dorsal root ganglia. ATP release in response to colorectal distension was measured by luminiscence. Results Rats with acute TNBS-colitis displayed significant visceral hypersensitivity that was dosedependently, but not fully, reversed by A-317491. Hypersenstivity was accompanied by an increased colonic release of ATP. Post-colitis rats also displayed visceral hypersensitivity that was dose-dependently reduced and fully normalized by A-317491 without increased PLOS ONE |
Gut, 2007
Background: Even though inflammation is a traditional tool for the induction of hyperalgesia in many tissues, recent observations suggest that not all inflammatory processes produce this change. Tolerance to colorectal distension (CRD) is reduced in patients with acute ulcerative colitis but is increased in patients with chronic inflammatory bowel disease. This suggests that the nature of the inflammatory infiltrate influences visceral perception. Aim: To test this hypothesis by assessing responses to CRD in mice with mild, acute or chronic colitis. Methods: CRD responses were measured in mice with mild non-specific colitis, and dextran sodium sulphate (DSS)-induced acute and chronic colitis. Responses were compared with tissue infiltrate and damage, interleukin (IL)1b and myeloperoxidase (MPO) activity and substance P, b-endorphin and m opioid receptor (MOR) expression. Results: Mild and acute colitis were associated with increased responsiveness to CRD. In contrast, CRD responses were not increased in mice with chronic colitis and this difference was not due to altered colonic wall compliance. MPO and IL1b levels were greater in acute than in chronic colitis. Larger increases in tissue substance P were seen in acute than in chronic DSS, whereas CD4 T cells, b-endorphin and MOR expression were evident only in chronic colitis. An inverse correlation was seen between substance P and MOR in these tissues. Conclusions: Acute colitis increased responsiveness to CRD and is accompanied by an acute inflammatory infiltrate and increased tissue substance P. Chronic DSS is accompanied by an increase in b-endorphin and MOR expression, and CD4 T cells, but no change in compliance or CRD responses. We conclude that acute inflammation generates hyperalgesia, whereas chronic inflammation involves infiltration by lymphocytes accompanied by MOR and b-endorphin up regulation, and this provides an antinociceptive input that restores normal visceral perception.
Visceral and Somatic Hypersensitivity in TNBS-Induced Colitis in Rats
Digestive Diseases and Sciences, 2008
Inflammation of visceral structures in rats has been shown to produce visceral/somatic hyperalgesia. Our objectives were to determine if trinitrobenzene sulfonic acid (TNBS) induced colitis in rats leads to visceral/somatic hypersensitivity. Male Sprague-Dawley rats (200g-250g) were treated with 20 mg of TNBS in 50% ethanol (n=40) or an equivalent volume of ethanol (n=40) or saline (n=25) via the colon. Colonic distension, Von-Frey, Hargreaves, and tail reflex test were used to evaluate for visceral, mechanical, and thermal sensitivity. The rats demonstrated visceral hypersensitivity at 2-28 days following TNBS (p<0.0001). The ethanol treated rats also demonstrated visceral hypersensitivity that resolved after day 14. TNBS treated rats demonstrated somatic hypersensitivity at days 14-28 (p<0.0001) in response to somatic stimuli of the hind-paw. TNBS colitis is associated with visceral and somatic hypersensitivity in areas of somatotopic overlap. This model of colitis should allow further investigation into the mechanisms of visceral and somatic hypersensitivity.
Effect of E. coli Nissle 1917 on post-inflammatory visceral sensory function in a rat model
Neurogastroenterology and Motility, 2005
Objective: Visceral hyperalgesia (VH) plays a key role for the manifestation of functional gastrointestinal (GI) disorders. In a subgroup of patients, the initial manifestation is preceded by GI inflammation. Recent studies have demonstrated an improvement of inflammation and symptoms during treatment with Escherichia coli Nissle 1917 (EcN). Aim: We aimed to characterize the effects of EcN on visceral sensitivity in a rat model of post-inflammatory VH. Methods: Male Lewis rats underwent colorectal instillation of trinitrobenzenesulphonic acid (TNBS) plus an equal amount of ethanol (test group) or physiological saline solution (control group). After 28, 35 and 42 days, standardized colorectal distensions were performed and the visceromotor reflex (VMR) of abdominal wall muscles was quantified by electromyographic recording. From day 28 onwards, EcN was administered in drinking water. Results: After TNBS, a significant increase of VMR was observed compared with saline controls over all study days. Administration of EcN reduced the TNBSinduced hyperalgesia [EcN: 863 ± 125 lV vs placebo: 1258 ± 157 lV (P < 0.05)] at day 35, while there were no significant alterations at any other study day.
Mechanisms contributing to visceral hypersensitivity: focus on splanchnic afferent nerve signaling
Neurogastroenterology & Motility, 2015
Background: Visceral hypersensitivity is a main characteristic of functional bowel disorders and is mediated by both peripheral and central factors. We investigated whether enhanced splanchnic afferent signaling in vitro is associated with visceral hypersensitivity in vivo in an acute and postinflammatory rat model of colitis. Methods: TNBS-colitis was monitored individually by colonoscopy to confimr colitis and follow convalescence and endoscopic healing in each rat. Experiments were performed in controls, rats with acute colitis and in post-colitis rats. Colonic afferent mechanosensitivity was assessed in vivo by quantifying visceromotor responses (VMRs), and by making extracellular afferent recordings from splanchnic nerve bundles in vitro. Multi-unit afferent activity was classified into single units identified as low threshold (LT), wide dynamic range (WDR), high threshold (HT) and mechanically insensitive afferents (MIA). Key results: During acute TNBS-colitis, VMRs were significantly increased and splanchnic nerve recordings showed proportionally less MIA and increased WDR and HT afferents. Acute colitis gave rise to an enhanced spontaneous activity of both LT and MIA and augmented afferent mechanosensitivity in LT, WDR and HT afferents. Post-colitis, VMRs remained significantly increased while splanchnic nerve recordings showed that the proportion of LT, WDR, HT and MIA had normalized to control values. However LT and MIA continued to show increased spontaneous activity and WDR and HT remained sensitized to colorectal distension. Conclusions & Inferences: Visceral hypersensitivity in vivo is associated with sensitized splanchnic afferent responses both during acute colitis and in the post-inflammatory phase. However splanchnic afferent subpopulations are affected differentially at both time points.
Role of sensory neurons in colitis: increasing evidence for a neuroimmune link in the gut
Inflammatory Bowel Diseases, 2011
Growing evidence suggests a crucial involvement of extrinsic sensory neurons in the aberrant immune response in colitis. Activation of sensory neurons is accompanied by a release of the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP), which induce neurogenic inflammation characterized by vasodilatation, plasma extravasation, and leukocyte migration. Although the role of these neuropeptides in experimental colitis and human inflammatory bowel disease (IBD) remains controversial, numerous data indicate a functional role for sensory neurons. In fact, chemical desensitization or surgical denervation of sensory nerves were shown to attenuate experimental colitis. Furthermore, pharmacological blockade of the neurokinin-1 (NK1) receptor was demonstrated to be efficient in chemically induced mouse models of colitis, and, intriguingly, also in immune-mediated models of colitis (T-cell transfer colitis). Finally, the genetic deletion or pharmacological blockade of receptor channels such as TRPV1 and TRPA1 on nociceptive sensory neurons was also demonstrated to be effective in treating experimental colitis, supposedly by inhibiting neuropeptide release. In summary, we are only beginning to understand the mechanisms of how sensory neurons modulate immune cellular actions. These findings highlight a new role of sensory neurons in chronic intestinal inflammation and suggest new avenues for therapy of IBD.
Colitis reduces short-circuit current response to inflammatory mediators in rat colonic mucosa
Inflammation, 1995
lnflammatory mediators may contribute to the diarrhea associated with colitis. Although the secretory action of such mediators is reported in normal tissue, there is little information regarding their effects on inflamed tissue. We examined the short-circuit current response (l~c) to these mediators, in mitomycin-C (MC)-induced colitis, a model with histological similarities to colitis in man. Rats were injected once with MC (3.25 mg/kg, intraperitoneally) or vehicle. The colons were removed three and seven days later and mounted, devoid of muscularis, in Ussing chambers for measurement of I~:, potential difference (PD), and resistance (Rt). MC-treated rats had diarrhea after three days, and microscopic studies revealed colonic inflammation. There were no significant differences in R,, PD, and Ix between control and MC-treated tissues at three and seven days. Maximal increases in I~ to bradykinin, prostaglandin E~, carbachol, substance P, and serotonin were depressed at three and/ or seven days after MC. The I~ response to theophylline was not affected. Theophylline activates secretion through an intracellular mechanism; the other agonists act by interaction with epithelial cell membranes. Therefore, the mechanism for the decreased I~c may result from uncoupling of receptors to second-messenger systems or desensitization of receptor-linked secretory mechanisms.
PLOS ONE, 2015
Objectives Experiments using P2X 3 knockout mice or more general P2X receptor antagonists suggest that P2X 3 receptors contribute to visceral hypersensitivity. We aimed to investigate the effect of the selective P2X 3 antagonist A-317491 on visceral sensitivity under physiological conditions, during acute colitis and in the post-inflammatory phase of colitis. Methods Trinitrobenzene sulphonic-acid colitis was monitored by colonoscopy: on day 3 to confirm the presence of colitis and then every 4 days, starting from day 10, to monitor convalescence and determine the exact timepoint of endoscopic healing in each rat. Visceral sensitivity was assessed by quantifying visceromotor responses to colorectal distension in controls, rats with acute colitis and post-colitis rats. A-317491 was administered 30 min prior to visceral sensitivity testing. Expression of P2X 3 receptors (RT-PCR and immunohistochemistry) and the intracellular signalling molecules cdk5, csk and CASK (RT-PCR) were quantified in colonic tissue and dorsal root ganglia. ATP release in response to colorectal distension was measured by luminiscence. Results Rats with acute TNBS-colitis displayed significant visceral hypersensitivity that was dosedependently, but not fully, reversed by A-317491. Hypersenstivity was accompanied by an increased colonic release of ATP. Post-colitis rats also displayed visceral hypersensitivity that was dose-dependently reduced and fully normalized by A-317491 without increased PLOS ONE |