Sex, serotonin and visceral hypersensitivity

描述(申请人提供)：肠易激综合征(IBS)是一种胃肠动力和内脏感觉障碍，在美国有3000万人受到影响。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中女性性激素的波动和压力有关。此外，作用于某些5-羟色胺(5-羟色胺)受体的药物可以缓解一些患者的IBS症状，包括内脏疼痛。最后，许多IBS患者在编码5-羟色胺转运体(SERT)的基因启动子区存在多态性。这种多态导致SERT的低表达。这些数据表明，5-羟色胺和女性性激素信号之间存在相互作用，从而导致IBS症状，特别是内脏疼痛。内脏疼痛的潜在病理生理学机制尚不清楚，部分原因是缺乏可以进行机械性和干预性研究的动物模型。我们将使用雄性和雌性5-羟色胺转运体(SERT)基因敲除(KO)大鼠来检验这一假设，我们提出的KO是一种性别特异性内脏高敏感性的动物模型。本项目将检验这一假设，即5-羟色胺(5-羟色胺，5-羟色胺)、促肾上腺皮质激素释放激素(CRH)和雌激素信号相互作用，增加供应结肠的初级传入神经元到第二级脊髓感觉神经元的神经传递，以及益生菌L.reuri(reuri乳杆菌6475)可用于安全有效地治疗IBS内脏疼痛。总体假设将在3个具体目标上进行检验。具体目标1将提出假设，即5-HT3和CRH1拮抗剂可以降低内脏超敏反应(VMR)，这是通过对结肠气囊扩张(CRD)的内脏运动反应(VMR)来衡量的。特定目的2将验证益生菌L.retueri可以降低雌性SERT KO大鼠内脏超敏反应的假说，该益生菌可能是一种安全有效的治疗IBS内脏疼痛的方法。《特定目标3》将测试5-羟色胺、17-β-β-羟色胺的假设 雌激素和促肾上腺皮质激素释放激素的相互作用改变了结肠投射感觉神经元的兴奋性，雌性SERT KO大鼠的结肠投射神经元的兴奋性将降低。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过敏的模型。

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.