Neurobiology of Corticotropin-Releasing Factor in the Enteric Nervous System during Stress

Abstract

Stress is associated with the onset, exacerbation, and reactivation of many gastrointestinal disorders, including irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD). Corticotropin-releasing factor (CRF) is a neuropeptide that plays a major role in the body’s overall responses to stress, including in the gut. The role of central CRF signaling pathways in stress-induced changes in gut motility has been well characterized. Recent studies suggest that peripheral CRF-related mechanisms also contribute to stress-induced changes in gut motility and intestinal mucosal function. CRF peptides (including CRF, urocortin 1, 2, and 3) and CRF receptors (i.e. CRF₁ and CRF₂) are present in the gut, especially in the enteric nervous system (ENS). CRF and urocortin 1 increase the excitability of ENS neurons via activation of CRF₁ receptors expressed by the neurons. Peripheral administration of CRF or urocortin 1 inhibits gastric emptying and motility through interaction with CRF₂ receptors in the stomach and stimulates colonic transit, motility and defecation via activation of CRF₁ receptors in the large intestine. The changes in gastrointestinal motility induced by peripheral CRF or urocortin 1 mimic those induced by acute stress. Moreover, peripheral injection of CRF receptor antagonists, which do not cross the blood-brain barrier, prevents acute stress-induced delayed gastric emptying and stimulation of colonic motor function. Acute stress, peripheral CRF and the selective CRF₁ receptor agonist increase the excitability of neurons in the colonic myenteric plexus. Acute and chronic stress increase intestinal ion secretion and mucosal permeability to macromolecules and cause diarrhea. Effects of stress on intestinal mucosal function are mimicked by peripheral injection of CRF and are suppressed by peripheral injection of nonselective peptide CRF receptor antagonists. Findings of this nature are strong evidence that activation of peripheral CRF receptors in the ENS is an important mechanism involved in stress-related alterations of gut motility and mucosal function.