Role of Corticotropin-releasing Hormone in Irritable Bowel Syndrome and Intestinal Inflammation

Corticotropin-releasing hormone (CRH) is a major mediator of stress response in the brain-gut axis. Irritable bowel syndrome (IBS) is presumed to be a disorder of the brain-gut link associated with exaggerated response to stress. We first showed that peripheral administration of CRH aggravated visceral sensorimotor function as well as adrenocorticotropic hormone (ACTH) response in IBS patients. We then administered alpha-helical CRH (alphahCRH), a non-selective CRH receptor antagonist among IBS patients. Electrical stimulation of the rectum induced significantly higher motility indices of the colon in IBS patients than in the controls. This response was significantly suppressed in IBS patients but not in the controls after administration of alphahCRH. Administration of alphahCRH induced a significant increase in the barostat bag volume of the controls but not in that of IBS patients. alphahCRH significantly reduced the ordinate scale of abdominal pain and anxiety evoked by electrical stimulation in IBS patients. Plasma ACTH and serum cortisol were generally not suppressed by alphahCRH. Last, administration of CRH1-receptor (CRH-R1) specific antagonist blocked colorectal distention-induced sensitization of the visceral perception in rats. Moreover, pretreatment with CRH-R1 antagonist blocked colorectal distention-induced anxiety, which was measured with elevated plus-maze, in rats. Evidence supporting the concept that peripheral CRH and CRH-R1 play important roles in brain-gut sensitization is increasing. Several studies have identified immunoreactive CRH and urocortin as well as CRH-R1 and CRH-R2 mRNAs in human colonic mucosa. In addition, reverse transcription-polymerase chain reaction has revealed the expression of CRH-R1 mRNA in both the myenteric and submucosal plexus in the guinea pig. Application of CRH has been shown to evoke depolarizing responses associated with elevated excitability in both myenteric and submucosal neurons. On the other hand, peripheral injection of CRH has been reported to induce discrete effects on colonic secretory and motor function, and permeability. There are functional differences between CRH-R1 and CRH-R2. For instance, activation of CRH-R1 causes a proinflammatory response, whereas stimulation of CRH-R2 provokes anti-inflammatory changes. In addition, there is evidence of the contrasting roles of CRH-R1 and CRH-R2 in visceral nociception. While CRH-R1 is involved in the pro-nociceptive effects of visceral pain, CRH-R2 mediates an anti-nociceptive response. These findings suggest the major role of CRH in stress-related pathophysiology of IBS and possibly in inflammation of the intestinal mucosa.