Beverley Greenwood-Van Meerveld

Fundamentals of Neurogastroenterology: Basic Science

This review examines the fundamentals of neurogastroenterology that may underlie the pathophysiology of functional GI disorders (FGIDs). It was prepared by an invited committee of international experts and represents an abbreviated version of their consensus document that will be published in its entirety in the forthcoming book and online version entitled ROME IV. It emphasizes recent advances in our understanding of the enteric nervous system, sensory physiology underlying pain, and stress signaling pathways. There is also a focus on neuroimmmune signaling and intestinal barrier function, given the recent evidence implicating the microbiome, diet, and mucosal immune activation in FGIDs. Together, these advances provide a host of exciting new targets to identify and treat FGIDs and new areas for future research into their pathophysiology.

Activation of colonic mucosal 5-HT(4) receptors accelerates propulsive motility and inhibits visceral hypersensitivity.

BACKGROUND & AIMS 5-hydroxytryptamine receptor (5-HT(4)R) agonists promote gastrointestinal motility and attenuate visceral pain, but concerns about adverse reactions have restricted their availability. We tested the hypotheses that 5-HT(4) receptors are expressed in the colonic epithelium and that 5-HT(4)R agonists can act intraluminally to increase motility and reduce visceral hypersensitivity. METHODS Mucosal expression of the 5-HT(4)R was evaluated by reverse-transcriptase polymerase chain reaction and immunohistochemical analysis of tissues from 5-HT(4)R(BAC)-enhanced green fluorescent protein mice. Amperometry, histology, and short-circuit current measurements were used to study 5-HT, mucus, and Cl(-) secretion, respectively. Propulsive motility was measured in guinea pig distal colon, and visceromotor responses were recorded in a rat model of colonic hypersensitivity. 5-HT(4)R compounds included cisapride, tegaserod, naronapride, SB204070, and GR113808. RESULTS Mucosal 5-HT(4) receptors were present in the small and large intestines. In the distal colon, 5-HT(4) receptors were expressed by most epithelial cells, including enterochromaffin and goblet cells. Stimulation of 5-HT(4)Rs evoked mucosal 5-HT release, goblet cell degranulation, and Cl(-) secretion. Luminal administration of 5-HT(4)R agonists accelerated propulsive motility; a 5-HT(4)R antagonist blocked this effect. Bath application of 5-HT(4)R agonists did not affect motility. Oral or intracolonic administration of 5-HT(4)R agonists attenuated visceral hypersensitivity. Intracolonic administration was more potent than oral administration, and was inhibited by a 5-HT(4)R antagonist. CONCLUSIONS Mucosal 5-HT(4) receptor activation can mediate the prokinetic and antinociceptive actions of 5-HT(4)R agonists. Colon-targeted, intraluminal delivery of 5-HT(4)R agonists might be used to promote motility and alleviate visceral pain, while restricting systemic bioavailability and resulting adverse side effects.

Esophageal hypersensitivity may be a major cause of heartburn

OBJECTIVE:Little is known about esophageal nociceptive thresholds in chronic heartburn sufferers with normal clinical findings. The aim of this study was to evaluate and to characterize the pathogenesis of heartburn in subjects who chronically use antacids and had not sought medical attention.METHODS:Subjects (N = 152) with chronic heartburn of ≥3 months duration underwent endoscopic grading of the esophagus, esophageal manometry, Bernstein testing, intraesophageal balloon distention (IEBD), and 24-h esophageal pH monitoring.RESULTS:Normal acid contact time (ACT ≤6%) was observed in 43% of these subjects with recurrent heartburn. Of subjects with normal ACT, 64% had normal LES pressure (≥10 mm Hg), 79% had normal esophageal endoscopy, 89% developed heartburn during Bernstein acid infusion, and 52% perceived IEBD as painful.CONCLUSIONS:Approximately 30% of individuals chronically using antacids for heartburn had esophageal sensitivity to mechanical or chemical stimuli despite negative endoscopy and pH monitoring. Our findings suggest that a significant subset of typical heartburn sufferers have a lower threshold for esophageal sensation and pain, which may influence options for pharmacological intervention in such subjects.

Stereotaxic delivery of corticosterone to the amygdala modulates colonic sensitivity in rats.

Episodes of anxiety are often associated with the onset or exacerbation of visceral pain in patients with irritable bowel syndrome (IBS). The central amygdaloid nucleus (CeA) is a key limbic structure involved in the expression of anxiety as well as a major site for regulating autonomic and visceral responses to stress. Previous experiments have shown that glucocorticoids can act directly at the CeA to increase the level of anxiety in rats. Therefore, the goal of this study was to examine the effect of stereotaxic delivery of corticosterone into the CeA on the development of visceral hypersensitivity by measuring visceromotor response to colorectal distention in rats. Stereotaxic delivery of corticosterone to the CeA increases indices of anxiety and produces a hypersensitive colon as demonstrated by an exaggerated visceromotor response to colorectal distention in the F344 rat strain. Our findings suggest that modulation of anxiety by manipulating amygdala function with corticosterone induced colonic hypersensitivity via descending neuronal pathways from the CeA.

Age-Associated Remodeling of the Intestinal Epithelial Barrier

Disorders of the gastrointestinal tract are common in the elderly people; however, the precise trait(s) of aging that contribute to the vulnerability of the gastrointestinal tract are poorly understood. Recent evidence suggests that patients with gastrointestinal disorders have increased intestinal permeability. Here, we address the hypothesis that disruption of the intestinal barrier is associated with aging. Our results demonstrated that permeability was significantly higher in colonic biopsies collected from old baboons compared with young baboons. Additionally, colonic tissue from the older animals had decreased zonula occluden-1, occludin, and junctional adhesion molecule-A tight junction protein expression and increased claudin-2 expression. Upregulation of miR-29a and inflammatory cytokines IFN-γ, IL-6, and IL-1β was also found in colonic biopsies from old baboons relative to young baboons. These results show for the first time that a pivotal contributing factor to geriatric vulnerability to gastrointestinal dysfunction may be increased colonic permeability via age-associated remodeling of intestinal epithelial tight junction proteins.

Inhibition of small intestinal secretion by cannabinoids is CB1 receptor-mediated in rats

We tested the hypothesis that cannabinoids, acting via a neuronal mechanism of action decrease small intestinal secretion. In vitro electrical stimulation induced ileal secretion in rats, that was attenuated by a cannabinoid receptor agonist, WIN 55212-2, (mesylate(R)-(+)-[2, 3-dihydro-5-methyl-3-[4-morpholino)methyl]pyrrolo-[1,2,3-de]-1, 4-benzoxazin-6-yl](1-naphthyl)methanone) but not its optical isomer WIN 55212-3. The inhibition of secretion induced by WIN 55212-2 was reversed by SR141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride), a cannabinoid CB1 receptor antagonist. An ileal secretory response stimulated by acetylcholine was unaffected by WIN 55212-2. These findings show that cannabinoids inhibit neurally mediated secretion via cannabinoid CB1 receptors. Thus, cannabinoids may have therapeutic potential for diarrhea unresponsive to available therapies.

Stress and the Microbiota–Gut–Brain Axis in Visceral Pain: Relevance to Irritable Bowel Syndrome

Visceral pain is a global term used to describe pain originating from the internal organs of the body, which affects a significant proportion of the population and is a common feature of functional gastrointestinal disorders (FGIDs) such as irritable bowel syndrome (IBS). While IBS is multifactorial, with no single etiology to completely explain the disorder, many patients also experience comorbid behavioral disorders, such as anxiety or depression; thus, IBS is described as a disorder of the gut–brain axis. Stress is implicated in the development and exacerbation of visceral pain disorders. Chronic stress can modify central pain circuitry, as well as change motility and permeability throughout the gastrointestinal (GI) tract. More recently, the role of the gut microbiota in the bidirectional communication along the gut–brain axis, and subsequent changes in behavior, has emerged. Thus, stress and the gut microbiota can interact through complementary or opposing factors to influence visceral nociceptive behaviors. This review will highlight the evidence by which stress and the gut microbiota interact in the regulation of visceral nociception. We will focus on the influence of stress on the microbiota and the mechanisms by which microbiota can affect the stress response and behavioral outcomes with an emphasis on visceral pain.

Divergent effects of amygdala glucocorticoid and mineralocorticoid receptors in the regulation of visceral and somatic pain

Elevated amygdala activity and increased responsiveness of the hypothalamic-pituitary-adrenal axis have been observed in irritable bowel syndrome (IBS) patients. Recently, we demonstrated that corticosterone (Cort) placed on the amygdala induced anxiety-like behavior coupled with decreased thresholds for visceral and somatic pain in rats. Moreover, these studies suggested that the effects of Cort were dependent on both the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR); however, the specific contributions of these receptors to the interaction between corticosteroids and the amygdala are still unclear. In the present study, we sought to define the distinct roles of amygdaloid GR and MR in anxiety-like behavior, visceral sensitivity, and somatic sensitivity through selective pharmacological activation. Male Fischer 344 rats received bilateral implants on the dorsal margin of the central amygdala containing the GR agonist dexamethasone (Dex), the MR agonist aldosterone (Aldo), or cholesterol as a control. Our results showed that GR or MR activation significantly reduced open arm exploration on the elevated plus maze, a measure of anxiety-like behavior. Aldo increased the number of abdominal muscle contractions in response to all levels of colorectal distension (CRD). In contrast, Dex only increased visceral sensitivity at noxious levels of CRD. Furthermore, GR but not MR activation reduced somatic pain thresholds measured by the mechanical force required to elicit hindlimb withdrawal. In summary, GR and MR mediated-mechanisms induce anxiety and visceral hypersensitivity, whereas somatic sensitivity involves only GR, suggesting that corticosteroids may enhance visceral and somatic sensation via divergent processes originating in the amygdala and involving specific steroid receptor mechanisms.

Elevated corticosterone in the amygdala leads to persistant increases in anxiety-like behavior and pain sensitivity

Corticosterone (CORT) localized to the amygdala induces anxiety-like behavior coupled with increased behavioral responses to visceral and somatic stimuli. In the current study, we investigated the long-term consequences of briefly exposing the amygdala to elevated levels of CORT with the hypothesis that modulation of the amygdala with CORT results in persistent increases in anxiety-like behavior and viscerosomatic sensitivity.

Attenuation by spinal cord stimulation of a nociceptive reflex generated by colorectal distention in a rat model

The mechanisms underlying the cause and treatment of visceral pain of gastrointestinal origin are poorly understood. Previous clinical studies have shown that spinal cord stimulation (SCS) attenuates neuropathic and ischemic pain, and animal experiments have provided knowledge about probable physiological mechanisms. The goal of the present study was to investigate whether SCS influences colonic sensitivity in a conscious rat. A visceromotor behavioral response (VMR), induced by colorectal distention, was used to quantify the level of colonic sensitivity. Under anesthesia, an electrode (cathode) was placed on the dorsal surface of the spinal cord at L1. One week after implantation of the SCS electrode, the effects of stimulation delivered with different intensities (50 Hz, 0.2 ms for 30 min) on colonic sensitivity were determined. Nociceptive levels of colorectal distention (60 mm Hg for 10 min) induced an enhanced VMR quantified as an increased number of abdominal muscle contractions compared to controls in which the balloon catheter was inserted into the colorectal region but not distended. Colonic sensitization with acetic acid increased the VMR to innocuous levels of colorectal distention (30 mm Hg for 10 min). We found that SCS induced a significant depression of the VMR produced by colorectal distention in both normal rats and those with sensitized colons. The suppressive effect of SCS on colonic sensitivity suggests that SCS may have therapeutic potential for the treatment of visceral pain of gastrointestinal origin associated with abdominal cramping and painful abdominal spasms.