Corticotropin-releasing factor receptors and stress-related alterations of gut motor function

Abstract

Over the past few decades, corticotropin-releasing factor (CRF) signaling pathways have been shown to be the main coordinators of the endocrine, behavioral, and immune responses to stress. Emerging evidence also links the activation of CRF receptors type 1 and type 2 with stress-related alterations of gut motor function. Here, we review the role of CRF receptors in both the brain and the gut as part of key mechanisms through which various stressors impact propulsive activity of the gastrointestinal system. We also examine how these mechanisms translate into the development of new approaches for irritable bowel syndrome, a multifactorial disorder for which stress has been implicated in the pathophysiology. Stress and gut motor functionA real or perceived threat to the homeostasis of mammalian organisms, originating internally or externally, triggers adaptive stress responses that affect behavior, as well as endocrine, immune, autonomic, and visceral functions (1, 2). Regarding effects in visceral functions in particular, early seminal investigations reported by Cannon and by Almy and colleagues provided clear evidence that emotional stress impacts gastric and colonic motor activity in healthy volunteers and cats (3, 4). Subsequent studies established that delayed emptying of the stomach is the most common response evoked by various acute stressors in both experimental animals and healthy human subjects (5). By contrast, in the colon, various stressors (including anxiety, dichotomous listening, fear, intermittent hand immersion in cold water, and stressful interviews) increase colonic motility in healthy subjects (5). Similarly, in rodents and dogs, stressors as diverse as open-field test, fear conditioning, loud sound, restraint, cold exposure, water avoidance, inescapable foot or tail shocks, and increased levels of cytokines induced by endotoxins stimulate propulsive colonic motor function (2, 5-7). The autonomic nervous system provides a peripheral neuronal network by which the effects of stress can be rapidly imposed on gut function. These are mediated through the sympathetic, and vagal and pelvic parasympathetic innervation of the enteric nervous system embedded into the muscular layers of the gut (8).It is becoming increasingly recognized that these interconnected brain-gut neuronal pathways activated during stress have relevance in the pathophysiology of functional bowel disorders (9-11). In particular, various stressors in the form of early life trauma, sexual abuse, maternal neglect, fear conditioning, lifethreatening events, and enteric infection have an important role in the etiology of irritable bowel syndrome (IBS), which is characterized by altered bowel movements, bloating, and visceral pain (10-13). Cyclic vomiting syndrome is another brain-gut disorder manifested by recurrent, stereotyped episodes of nausea and vomiting in the pediatric population, which is triggered by stressors related to heightened emotional state, fasting, exercise, and infection in 80% of the patients (14).A big step forward...

Review article: associations between immune activation, intestinal permeability and the irritable bowel syndrome

“…For example, stress or depression can induce sensorymotor alterations in the gut and may be associated with a subsequent 'top-down' induced inflammatory response. [120][121][122][123][124][125] Many other risk factors, such as surgery, exposure to anaesthesia, diet or food allergies, could also have as-yet unknown impacts on the immune system in IBS. This idea highlights one of the major limitations of the current data: with the exception of the IBS-PI subtype, the question of whether inflammation is a cause or a consequence of IBS remains to be addressed.…”

MOLECULAR EVOLUTION OF GPCRS: CRH/CRH receptors

“…A large number of studies on humans, rodents, cats and dogs have demonstrated that diverse stressful stimuli induce a variety of actions on the GI tract that typically include delayed gastric emptying and colonic motor activity (Tache et al 2001, Tache & Bonaz 2007. Although activation of the autonomic nervous system is responsible for regulation of gastric physiology, CRH receptors in the Vertebrate CR2…”

Mechanism(s) of in utero meconium passage

“…Stress and gut motility: lessons learned from laboratory animals Although impact of emotional stress on gastric and colonic motor activity has long been known in humans only during the past two decades, much attention has been paid to understand the neural circuitry and hormonal effectors that mediate effects of stress on gut functions in animal models (see review 7,8 ). The rat is a widely used animal model for stress-related alteration on gut motor functions, although limited investigation has also been performed in mouse models.…”

“…15 Anatomical, physiological, pharmacological and biochemical studies have provided unambiguous evidence that the CRF system (CRF, urocortins, CRF-R1 and CRF-R2) is the key player of gastrointestinal motility disturbance during times of stress. 7,16 Hypothesis: in utero meconium passage is a fetal neurovisceral motor response to stress We hypothesize that in utero meconium passage is a neurovisceral motor response to fetal stress and that the CRF system plays a critical role in the stimulation of cholinergically mediated fetal colonic propulsive motor functions that trigger meconium passage. An integrated model proposed for fetal in utero meconium passage is shown in Figure 1.…”