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

脑-肠相互作用是大脑和肠道之间的功能性和相互联系。脑-肠相互作用是发育中的古老现象，但尚未得到充分研究。这些现象有两个主要方向。一种是通过自主神经和/或内分泌途径通过应激诱导的大脑兴奋来改变肠道功能。另一种是通过内脏传入通路，通过来自肠道的感知信号改变大脑功能。我们假设，促肾上腺皮质激素释放激素（CRH）和相关的神经递质可能被释放在特定区域的大脑由心理社会压力或内脏刺激，这些现象可能会增加肠易激综合征（IBS）患者。本研究的主要目的是通过动物实验和临床脑肠道检查（包括正电子发射断层扫描（PET）和脑电图（EEG）定量分析）来验证我们的假设。利用该基金（2003-2006），我们成功地开发了模拟IBS病理生理学的大鼠。施用特异性CRH-R1拮抗剂逆转了大鼠的IBS样病理生理学。人体内脏刺激会引起腹痛和局部脑血流量增加。内脏刺激激活的特定区域是丘脑和边缘皮质。内脏刺激也改变了脑电功率谱和地形图。内脏刺激还改变内脏感觉、焦虑和胃肠动力。这些现象在IBS患者中被夸大，CRH拮抗剂的给药逆转了IBS的病理生理学。这些发现表明，在特定的大脑或其他器官中释放的CRH可能在IBS和模拟IBS的动物中发挥重要作用。因此，利用该基金（2003-2006），我们成功地阐明了CRH在脑肠相互作用中的一些基本作用。本课题组对这一范式的进一步研究寄予厚望。

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.