Sex, serotonin and visceral hypersensitivity

性、血清素和内脏过敏

• 批准号: 9189713
• 负责人: James J. Galligan
• 金额: $ 33.42万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9189713
• 关键词: Acute; Affect; Afferent Neurons; Animal Model; Bacteria; CRF receptor type 1; Cations; Cavia; Chronic; Colon; Colorectal; Corticotropin-Releasing Hormone; Data; Electrophysiology (science); Estradiol; Estrogens; Exposure to; Female; Functional disorder; GPER gene; Gastrointestinal Motility; Genes; Genetic Polymorphism; Gonadal Steroid Hormones; Granisetron; Hypersensitivity; In Vitro; Individual; Intervention Studies; Irritable Bowel Syndrome; Knock-out; Lactobacillus reuteri; Libraries; Measures; Messenger RNA; Modeling; Mutate; Neurons; Nociception; Pain; Pain Disorder; Patients; Peristalsis; Pharmaceutical Preparations; Pharmacology; Physiology; Preparation; Principal Investigator; Probiotics; Promoter Regions; Property; Rattus; Sensation Disorders; Serotonin; Serotonin Receptors 5-HT-3; Severities; Signal Transduction; Specificity; Spinal; Spinal Ganglia; Spinal cord posterior horn; Stress; Study models; Symptoms; Testing; Tissue Harvesting; United States; Visceral; Visceral Afferent Neuron; Visceral pain; Whole-Cell Recordings; Woman; afferent nerve; antagonist G; antalarmin; effective therapy; gastrointestinal; in vivo; male; men; motility disorder; mutant; nerve supply; neurotransmission; novel; novel therapeutics; programs; public health relevance; response; serotonin receptor; serotonin transporter; sex; subcutaneous; tissue culture

DESCRIPTION (provided by applicant): Irritable bowel syndrome (IBS) is a gastrointestinal motility and visceral sensation disorder that affects 30 million people in the United States. IBS is twice as common in women as men and IBS symptom severity is related to fluctuations in circulating female sex hormones and to episodes of stress. In addition, drugs which act at some 5-hydroxytryptamine (5- HT serotonin) receptors relieve IBS symptoms, including visceral pain, in some patients. Finally, many IBS patients have a polymorphism in the promoter region of the gene that encodes the serotonin transporter (SERT). This polymorphism leads to low SERT expression. These data indicate that there is an interaction between serotonin and female sex hormone signaling that leads to IBS symptoms especially visceral pain. The underlying pathophysiology of visceral pain is unclear and this is partly due to a lack of animal models where mechanistic and interventional studies can be conducted. We will use This hypothesis will be tested using male and female serotonin transporter (SERT) knockout (KO) rats, which we propose is an animal model of sex specific visceral hypersensitivity. This project will test th hypothesis that 5-hydroxytryptamine (5-HT, serotonin) corticotropin releasing hormone (CRH) and estrogen signaling interact to increase neurotransmission of primary afferent neurons supplying the colon to second order spinal sensory neurons and that probiotic bacteria L. reuteri (Lactobacillus reuteri 6475) can be used as a safe and effective treatment for visceral pain in IBS. The overall hypothesis will be tested in 3 specific aims. Specific aim 1 will tes the hypothesis that 5-HT3 and CRH1 antagonists can reduce visceral hypersensitivity as measured by the visceromotor response (VMR) to colorectal balloon distention (CRD). Specific aim 2 will test the hypothesis that the probiotic bacteria L. retueri can reduce visceral hypersensitivity in female SERT KO rats and this this probiotic may be a safe and effective treatment for visceral pain in IBS. Specific aim 3 will test the hypothesis that serotonin, 17-beta estradiol and CRH interaction to alter the excitability of colon projecting sensory neurons and that colon projecting neurons from female SERT KO rats will show reduced excitability. The data would indicate that the SERT KO rat is a model for studying changes in the sensory nerve supply of the gut that leads to visceral hypersensitivity.

描述（由申请人提供）：肠易激综合症 (IBS) 是一种胃肠动力和内脏感觉障碍，影响着美国 3000 万人。 IBS 在女性中的发病率是男性的两倍，IBS 症状的严重程度与循环女性性激素的波动和压力发作有关。 此外，作用于某些 5-羟色胺（5-HT 血清素）受体的药物可缓解某些患者的 IBS 症状，包括内脏疼痛。 最后，许多 IBS 患者在编码血清素转运蛋白 (SERT) 的基因启动子区域存在多态性。 这种多态性导致 SERT 表达低。 这些数据表明，血清素和女性性激素信号之间存在相互作用，导致肠易激综合症症状，尤其是内脏疼痛。 内脏疼痛的潜在病理生理学尚不清楚，部分原因是缺乏可以进行机制和介入研究的动物模型。我们将使用雄性和雌性血清素转运蛋白（SERT）敲除（KO）大鼠来测试这一假设，我们认为这是一种性别特异性内脏超敏反应的动物模型。 该项目将测试以下假设：5-羟色胺（5-HT，血清素）促肾上腺皮质激素释放激素 (CRH) 和雌激素信号相互作用，增加初级传入神经元的神经传递，为结肠提供二级脊髓感觉神经元，并且益生菌罗伊氏乳杆菌（罗伊氏乳杆菌 6475）可安全有效地治疗 IBS 内脏疼痛。 总体假设将在 3 个具体目标中进行检验。 具体目标 1 将检验以下假设：5-HT3 和 CRH1 拮抗剂可以降低内脏超敏性（通过对结直肠球囊扩张 (CRD) 的内脏运动反应 (VMR) 来测量）。 具体目标 2 将检验益生菌 L. retueri 可以降低雌性 SERT KO 大鼠的内脏过敏性的假设，并且这种益生菌可能是治疗 IBS 内脏疼痛的安全有效的方法。具体目标 3 将检验以下假设：血清素 17-β 雌二醇和 CRH 相互作用可改变结肠投射感觉神经元的兴奋性，并且雌性 SERT KO 大鼠的结肠投射神经元将表现出兴奋性降低。 这些数据表明 SERT KO 大鼠是研究肠道感觉神经供应变化导致内脏超敏反应的模型。