Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with irritable bowel syndrome

Abstract

Background and aims: Corticotropin releasing hormone (CRH) is a major mediator of the stress response in the brain-gut axis. Irritable bowel syndrome (IBS) is presumed to be a disorder of the brain-gut link associated with an exaggerated response to stress. We hypothesised that peripheral administration of a-helical CRH (ahCRH), a non-selective CRH receptor antagonist, would improve gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation in IBS patients. Methods: Ten normal healthy subjects and 10 IBS patients, diagnosed according to the Rome II criteria, were studied. The tone of the descending colon and intraluminal pressure of the sigmoid colon were measured at baseline, during rectal electrical stimulation (ES), and at recovery after administration of saline. Visceral perception after colonic distension or rectal ES was evaluated as threshold values on an ordinate scale. The same measurements were repeated after administration of ahCRH (10 mg/kg). Results: ES induced significantly higher motility indices of the colon in IBS patients compared with controls. This response was significantly suppressed in IBS patients but not in controls after administration of ahCRH. Administration of ahCRH induced a significant increase in the barostat bag volume of controls but not in that of IBS patients. ahCRH significantly reduced the ordinate scale of abdominal pain and anxiety evoked by ES in IBS patients. Plasma adrenocorticotropic hormone and serum cortisol levels were generally not suppressed by ahCRH. Conclusion: Peripheral administration of ahCRH improves gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation, without affecting the hypothalamo-pituitary-adrenal axis in IBS patients.

Inhibition of Inflammatory Pain by CRF at Peripheral, Spinal and Supraspinal Sites: Involvement of Areas Coexpressing CRF Receptors and Opioid Peptides

“…In light of the recent increasing interest in the potential modulating effects of CRF in clinically relevant pain conditions such as visceral pain (Nozu and Kudaira, 2006;Sagami et al, 2004), postoperative joint pain (Likar et al, 2007), and fibromyalgia (McLean et al, 2006;Lund et al, 2006), we set out to investigate systematically the antinociceptive effects of CRF at the three main levels of the neuraxis of pain transmission, that is, at the level of the brain, spinal cord, and periphery. As it was suggested that antinociceptive effects of CRF are identified rather in tonic than in phasic pain (Lariviere and Melzack, 2000), we have chosen an animal model of tonic pain, that is, Freunds complete adjuvant (FCA) hindpaw inflammation.…”

The stressed gut: Contributions of intestinal stress peptides to inflammation and motility

“…Central and systemic CRF and Ucns induce the symptoms of this syndrome, and antagonists blunt the effects of stress on the gut (3,4). A CRF-R1 antagonist also suppresses the colonic motility and pain responses to colonic distension and stimulation of the rectal mucosa in patients with irritable bowel syndrome (15). Additional mechanistic studies, such as that of la Fleur et al, are clearly warranted to further our understanding of the intestinal stress response system in diseases and the physiological regulation of digestion.…”

Intravenous Corticotropin-releasing Hormone Administration Increases Esophageal Electrical Sensitivity in Healthy Individuals

“…18 Another study reported that when a-helical CRH was peripherally administered in IBS patients, the hyperresponsiveness to stress induced by colonic electrical stimulation was suppressed. 8 These results indicate that stress is closely associated with colonic perception and bowel movements. Previous animal studies have analyzed esophageal perception after stress loading.…”

“…6 Central and gastrointestinal responses to stress can be pronounced, particularly in patients with FGID such as IBS. 7,8,15,16 The association between stress and visceral perception has been reported in a number of colonic studies. Fukudo et al 17 showed…”

“…6,7 Gastrointestinal physiologies, such as colonic motor and sensory functions, are known to be altered by stress induced by intravenous administration of CRH in patients with irritable bowel syndrome (IBS). 8,9 This evidence suggests that altered brain-gut interactions resulting from a magnified response to CRH lead to changes in colonic functions and could be relevant to the pathophysiology of IBS. However, the influence of CRH on the esophagus has not yet been fully elucidated.…”