From Hans Selye's Discovery of BiologicalStress to the Identification of Corticotropin-Releasing Factor Signaling Pathways Implication in Stress-relatedFunctional Bowel Diseases

摘要

Selye pioneered the concept of biological stress in 1936, culminating in the identifica-tion of the corticotropin-releasing factor (CRF) signaling pathways by Vale's group in the last two decades. The characterization of the 41 amino-acid CRF and other peptide members of the mammalian CRF family, urocortin 1, urocortin 2, and urocortin 3, and the cloning of CRF1 and CRF2 receptors, which display distinct affinity for CRF ligands, combined with the development of selective CRF receptor antagonists enable us to unravel the importance of CRF1 receptor in the stress-related endocrine (activation of pituitary-adrenal axis), behavioral (anxiety/depression, altered feeding), autonomic (ac-tivation of sympathetic nervous system, and immune responses. The activation of CRF1 receptors is also one of the key mechanisms through which various stressors impact the gut to stimulate colonic propulsive motor function and to induce hypersensitivity to colorectal distension as shown by the efficacy of the CRF1 receptor antagonists in blunting these stress-related components. The importance of CRF1 signaling pathway in the visceral response to stress in experimental animals provided new therapeutic ap-proaches for treatment of functional bowel disorder such as irritable bowel syndrome, a multifactor functional disorder characterized by altered bowel habits and visceral pain, for which stress has been implicated in the pathophysiology and is associated with anxiety-depression in a subset of patients.