Role of Corticotropin-releasing Factor Signaling in Stress-related Alterations of Colonic Motility and Hyperalgesia

Abstract

The corticotropin-releasing factor (CRF) signaling systems encompass CRF and the structurally related peptide urocortin (Ucn) 1, 2, and 3 along with 2 G-protein coupled receptors, CRF1 and CRF2. CRF binds with high and moderate affinity to CRF1 and CRF2 receptors, respectively while Ucn1 is a high-affinity agonist at both receptors, and Ucn2 and Ucn3 are selective CRF2 agonists. The CRF systems are expressed in both the brain and the colon at the gene and protein levels. Experimental studies established that the activation of CRF1 pathway in the brain or the colon recaptures cardinal features of diarrhea predominant irritable bowel syndrome (IBS) (stimulation of colonic motility, activation of mast cells and serotonin, defecation/watery diarrhea, and visceral hyperalgesia). Conversely, selective CRF1 antagonists or CRF1/CRF2 antagonists, abolished or reduced exogenous CRF and stress-induced stimulation of colonic motility, defecation, diarrhea and colonic mast cell activation and visceral hyperalgesia to colorectal distention. By contrast, the CRF2 signaling in the colon dampened the CRF1 mediated stimulation of colonic motor function and visceral hyperalgesia. These data provide a conceptual framework that sustained activation of the CRF1 system at central and/or peripheral sites may be one of the underlying basis of IBS-diarrhea symptoms. While targeting these mechanisms by CRF1 antagonists provided a relevant novel therapeutic venue, so far these promising preclinical data have not translated into therapeutic use of CRF1 antagonists. Whether the existing or newly developed CRF1 antagonists will progress to therapeutic benefits for stress-sensitive diseases including IBS for a subset of patients is still a work in progress.

Mast Cells and Irritable Bowel Syndrome: From the Bench to the Bedside

“…62,84 Plenty of work has been done to verify the concept that MCs contribute to stress induced gut dysfunction. For example, MCs mediate stress induced intestinal barrier disruption [85][86][87] and visceral hypersensitivity 82,88,89 due to the release of tryptase, TNF-α, 86 and histamine. 82 Peripheral administration of H 1 R antagonists fexofenadine and ebastine are capable of reversing post stress visceral hypersensitivity in rats.…”

Repeated Water Avoidance Stress Alters Mucosal Mast Cell Counts, Interleukin-1β Levels with Sex Differences in the Distal Colon of Wistar Rats

“…4 Stress induces changes of colonic functions, including increase of permeability, mucus secretion, motility, myenteric nerve activation, serotonin release, and the development of visceral hypersensitivity in rats. [5][6][7] In particular, water avoidance stress (WAS) is a well-known animal model of stress that increases the psychological component and imitates the experience of ongoing environmental life in humans. 8 It has been revealed that WAS increased fecal pellet output (FPO), colonic mast cell count, mucosal cytokine levels, and intestinal permeability.…”

Intravenous Corticotropin-releasing Hormone Administration Increases Esophageal Electrical Sensitivity in Healthy Individuals

“…Recent studies have reported that an important factor in the pathogenesis of non-erosive reflux disease (NERD), functional dyspepsia, and IBS may be hyperresponsiveness to stress in the gastrointestinal tract. 9,[12][13][14] In daily life, we experience various symptoms due to excessive "stress" on the body. When the human brain perceives stress, CRH is released from the hypothalamus.…”

“…6,7 Gastrointestinal physiologies, such as colonic motor and sensory functions, are known to be altered by stress induced by intravenous administration of CRH in patients with irritable bowel syndrome (IBS). 8,9 This evidence suggests that altered brain-gut interactions resulting from a magnified response to CRH lead to changes in colonic functions and could be relevant to the pathophysiology of IBS. However, the influence of CRH on the esophagus has not yet been fully elucidated.…”