Article

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

Tohoku University, Sendai-shi, Miyagi, Japan
Gut (Impact Factor: 14.66). 08/2004; 53(7):958-64. DOI: 10.1016/S0016-5085(03)82897-4
Source: PubMed

ABSTRACT

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 alpha-helical CRH (alphahCRH), a non-selective CRH receptor antagonist, would improve gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation in IBS patients.
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 alphahCRH (10 micro g/kg).
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 alphahCRH. Administration of alphahCRH induced a significant increase in the barostat bag volume of controls but not in that of IBS patients. alphahCRH 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 alphahCRH.
Peripheral administration of alphahCRH improves gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation, without affecting the hypothalamo-pituitary-adrenal axis in IBS patients.

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    • "In IBS patients, the exogenous administration of CRH induced robust colonic motility[24]. Electrical stimulation of the rectum induced an increase in motility indices in IBS patients and this response was inhibited by the administration of a CRH antago- nist[28]. Therefore, dysfunction of CRH signaling is considered to be related to the pathophysiology of IBS. "
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    ABSTRACT: Corticotropin-releasing hormone (CRH) plays an important role in the pathophysiology of irritable bowel syndrome (IBS) and regulates the stress response through two CRH receptors (R1 and R2). Previously, we reported that a CRHR1 gene polymorphism (rs110402, rs242924, and rs7209436) and haplotypes were associated with IBS. However, the association between the CRHR2 gene and IBS was not investigated. We tested the hypothesis that genetic polymorphisms and haplotypes of CRHR2 are associated with IBS pathophysiology and negative emotion in IBS patients.
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    • "In patients with chronic pain, CRF concentration within the cerebrospinal fluid correlated with pain rating (McLean et al., 2006) and a selective CRF 1 antagonist decreased enhanced amygdala activity and emotional ratings (Hubbard et al., 2011), suggesting that CRF is a valid target for therapeutic intervention in some chronic pain conditions. However, clinical evidence to date has produced mixed effects on pain relief in this therapeutic class (Sagami et al., 2004; Sweetser et al., 2009). Pituitary Adenylate Cyclase–Activating Polypeptide Receptors. "
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    • "CRH expression and biological function are mediated by its membrane receptors, CRH-R1 and CRH-R2 (Grammatopoulos, 2012). CRH is involved in the pathogenesis of a number of inflammatory disorders, such as allergic diseases (Vasiadi et al., 2012), irritable bowel syndrome (Sagami et al., 2004) and some pain syndromes (La et al., 2008). CRH can also activate microglia in the process of neuropathology (Wang et al., 2007), but the underlying mechanism is not fully understood. "
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