From Hans Selye's Discovery of Biological Stress to the Identification of Corticotropin‐ Releasing Factor Signaling Pathways

Abstract

Selye’s pioneer the concept of biological stress in 1936 culminating to the identification 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, the cloning of CRF1 and CRF2 receptors, which display distinct affinity for CRF ligands, combined with the development of selective CRF receptor antagonists enable to unravel the importance of CRF1 receptor in the stress-related endocrine (activation of pituitary-adrenal axis), behavioral (anxiety/depression, altered feeding), autonomic (activation of sympathetic nervous system) and immune responses. The activation of CRF1 receptors is also part of 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 pathways in the visceral response to stress in experimental animals provided new therapeutic approaches 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 subset of patients.

Selye’s general adaptation syndrome: stress-induced gastro-duodenal ulceration and inflammatory bowel disease

“…This effect of stress is probably mediated by the sympathomedullary system and corticotrophin-releasing factor (CRF) acting both centrally and within the gut (Bunnett 2005, Tache et al 2008, Lukewich et al 2014. Notwithstanding the possible role of stress in bowel disorders and the fact that CRF and its receptors are regarded by some as potentially relevant therapeutic targets (Tache et al 2008), it must be stressed that the signal factors that trigger IBD and related disorders remain to be determined. The story is far from complete.…”

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

“…Of note is also the inhibitory effects of CRF 2 receptor activation on stress-related gut motility and sensitization, as a gut stress coping system and the possible CRF 1 -CRF 2 cross talk in the colon 54,176,203 and the brain 204 that need to be taken into consideration in targeting CRF signaling for gut centric intestinal secretomotor alterations and visceral pain therapeutic purposes. CRF being pivotal in the body's response to stressful stimuli and the extensive preclinical data indicating that dysregulation of CRF-CRF 1 system is implicated in the etiology and maintenance of several stress-sensitive disorders as recently reviewed, 20,[205][206][207] a better understanding of CRF signaling is likely to provide novel insights in the otherwise challenging pathophysiology of functional gut diseases such as IBS.…”

“…18 In particular one of the key mediator in the bodily response to various stressors and the brain-gut interactions is the corticotrophin releasing factor (CRF) pathways family. [19][20][21] In this review, we will first briefly outlined the components of the mammalian CRF signaling systems that encompasses CRF peptides, receptors and signaling pathways. We will review preclinical findings on the actions of CRF in the brain and the colon to mimic stress-related stimulation of colonic secretory-motor function and the development of visceral hyperalgesia as well as the role of CRF receptor subtypes in these colonic responses to stress.…”

Experimental Models of Irritable Bowel Syndrome and the Role of the Enteric Neurotransmission

“…Preclinical evidence has accumulated over the years suggesting that stress-related alterations of colonic motor and visceral functions are primarily mediated by the activation of brain CRFr/CRF1 signaling pathway, while CRF2 receptor activation may exert a counteracting influence (39)(40)(41). CRFr are located in effector neurons of the hypothalamus, the amygdala, the cingulate cortex and the locus caeruleus complex.…”