Sex, serotonin and visceral hypersensitivity

描述（由申请人提供）：肠易激综合征（IBS）是一种胃肠动力和内脏感觉障碍，影响美国3000万人。 IBS在女性中是男性的两倍，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- 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5-羟色胺转运蛋白（SERT）的基因的启动子区具有多态性。 这种多态性导致低SERT表达。 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IBS症状，特别是内脏疼痛。 内脏痛的潜在病理生理学尚不清楚，部分原因是缺乏可进行机制和干预研究的动物模型。我们将使用雄性和雌性5-羟色胺转运体（SERT）敲除（KO）大鼠来检验这一假设，我们提出这是一种性别特异性内脏高敏感性的动物模型。 本项目将验证以下假设：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，以增加初级传入神经元向二级脊髓感觉神经元供应结肠的神经传递，以及益生菌L.罗伊氏乳杆菌（Lactobacillus reuteri 6475）可作为IBS内脏痛的安全有效的治疗方法。 将在3个具体目标中检验总体假设。 具体目标1将测试5-HT 3和CRH 1拮抗剂可以降低内脏高敏感性的假设，如通过内脏对结肠直肠球囊扩张（CRD）的反应（VMR）所测量的。 具体目标2将检验益生菌L. retueri可以降低雌性SERT KO大鼠的内脏高敏感性，这种益生菌可能是IBS内脏疼痛的安全有效的治疗方法。具体目标3将检验血清素17-β 雌二醇和CRH相互作用改变结肠投射感觉神经元的兴奋性，并且来自雌性SERT KO大鼠的结肠投射神经元将显示降低的兴奋性。 数据表明，SERT KO大鼠是研究导致内脏高敏感性的肠道感觉神经供应变化的模型。

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.