Role of Stress-related Peptide CRH in Brain-Gut Interactions

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Brain-gut interactions are functional and reciprocal connection between the brain and the gut. Brain-gut interactions are the developmentally old phenomena but are not fully investigated. There are two major directions in these phenomena. One is changing the gut function by stress-induced excitation of the brain via autonomic and/or endocrine pathways. The other is changing the brain function by the perception signal from the gut via visceral afferent pathways. We hypothesized that corticotropin-releasing hormone (CRH) and related neurotransmitters may be released in the specific regions of the brain by psychosocial stress or visceral stimulation and that these phenomena may be augmented in patients with irritable bowel syndrome (IBS). The main objective of this research is to test our hypotheses by animal experiments and clinical brain-gut examination including positron emission tomography (PET) and quantitative analysis of electroencephalography (EEG). Using this grant (2003-2006), we successfully developed rats mimicking pathophysiology of IBS. Administration of specific CRH-Rl antagonist reversed the IBS-like pathophysiology of rats. Visceral stimulation in humans induced abdominal pain and increase in regional cerebral blood flow. The specific regions activated by visceral stimulation were thalamus and the limbic cortices. EEG power spectra and topogram were also changed by visceral stimulation. The visceral stimulation also changed visceral sensation, anxiety, and gastrointestinal motility. These phenomena were exaggerated in IBS patients and administration of CRH antagonist reversed the IBS pathophysiology. These findings suggest that released CRH in the specific brain or in the other organs may play a major role of IBS and animals mimicking IBS. Thus using this grant (2003-2006), we succeeded to clarify some fundamental roles of CRH in brain-gut interactions. Further investigation on this paradigm is highly expected by our research group.