Corticotropin releasing factor signaling in colon and ileum: regulation by stress and pathophysiological implications

Abstract

It is well established that central corticotropin releasing factor (CRF) signaling mediates the gastrointestinal responses to stress. However, as shown in the brain, both CRF receptors and ligands are also widely expressed in the colon and the ileum of humans and rodents, and stress modulates their expression. Several functional studies documented that peripheral injection of CRF or urocortin stimulates colonic transit, motility, Fos expression in myenteric neurons, and defecation through activation of CRF(1) receptors, whereas it decreases ileal contractility via CRF(2) receptors. Additionally, intraperitoneal administration of CRF induces colonic mast cells degranulation via both CRF(1) and CRF(2) receptors and increases ion secretion and mucosal permeability to macromolecules, which can in turn promote intestinal inflammation and alter visceral sensitivity. Most peripheral CRF-induced alterations of colonic and ileal functions mimic effects which are observed after stress exposure, and CRF receptor antagonists given peripherally prevent stress-induced GI dysfunction. Furthermore, CRF peptides can reproduce secretomotor and mucosal alterations in vitro. Therefore, accumulated clinical and preclinical evidence supports in addition to the brain, a role for peripheral CRF signaling in mediating stress-induced effects on gastrointestinal sensorimotor, mucosal and immune functions, that may be components of underlying mechanisms involved in stress-related impact on inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS).