Investigation of Cell-Type Specific Contributions to Bladder Pain Modulation in the Central Amygdala

项目摘要 泌尿系慢性骨盆疼痛（UCPP）综合征是最常见的慢性内脏疼痛疾病， 影响了美国500万到1000万人UCPP缺乏有效的治疗方法， 这可能是由于，部分原因是未能理解中枢神经系统对神经系统调节的贡献。 疾病最近的证据表明杏仁核的中央核是大脑皮层的一个重要区域， 膀胱疼痛的病理学来自人类和啮齿动物模型的证据表明， 杏仁核对疼痛的调制有不同的贡献。UCPP患者表现出侧化的变化， 与健康患者和患有其他内脏疼痛的患者相比，杏仁核功能连接 条件最近，研究表明，左右中央杏仁核在大脑皮层中具有不同的功能。 在小鼠膀胱疼痛的背景下。我们的目标是进一步探索这种偏侧化，以确定分子 调制器负责驱动这些差分功能。降钙素基因相关肽（CGRP）是一种 神经肽，分别已被证明在中枢神经系统中具有促伤害感受功能和抗伤害感受功能 杏仁核我们的初步数据表明，CGRP活性显示出有趣的不对称性的背景下， 膀胱疼痛，右侧中央杏仁核中的CGRP驱动膀胱疼痛，但左侧中央杏仁核中的CGRP驱动膀胱疼痛 扁桃体阻塞膀胱疼痛本提案的目标是了解CGRP如何促进 左和/或右中央杏仁核中膀胱疼痛的差异调节。我们将通过以下方式实现这一目标：1） 探讨中央杏仁核内表达CGRP的脑干投射对脑缺血后海马神经元生理功能的影响。 对膀胱刺激的反应和2）研究这些相同的CGRP细胞对膀胱刺激的作用。 使用炎性膀胱疼痛的小鼠模型调节清醒动物的疼痛样行为。这些 实验将不仅有助于确定CGRP在膀胱疼痛的差异处理中的程度， 左、右中央杏仁核，但也提供了一个更好的理解的贡献机制， UCPP，因此为患者提供更先进和有效的CNS靶向治疗。

Project Summary Urologic chronic pelvic pain (UCPP) syndromes are the most common chronic visceral pain conditions, affecting between 5 and 10 million people in the United States. The lack of effective treatments for UCPP is likely due, in part, to a failure to understand the central nervous system's contribution to the modulation of the disease. Recent evidence has implicated the central nucleus of the amygdala as an important region in the pathology of bladder pain. Evidence from both human and rodent models indicates that the left and right amygdala have different contributions to the modulation of pain. UCPP patients exhibit lateralized changes in amygdala functional connectivity compared to healthy patients and patients suffering from other visceral pain conditions. Recently, the right and left central amygdala has been shown to have divergent functions in the context of bladder pain in mice. We aim to further explore this lateralization in order to determine molecular modulators responsible for driving these differential functions. Calcitonin gene related peptide (CGRP) is a neuropeptide that separately has been shown to have both pro- and anti-nociceptive functions in the central amygdala. Our preliminary data indicates that CGRP activity shows interesting asymmetries in the context of bladder pain, with CGRP in the right central amygdala driving bladder pain but CGRP in the left central amygdala blocking bladder pain. The goal of this proposal is to understand how CGRP contributes to the differential modulation of bladder pain in the left and/or right central amygdala. We will approach this goal by 1) exploring the influence of brainstem CGRP-expressing projections in the central amygdala on the physiological response to bladder stimulation and 2) investigating the contribution of these same CGRP cells on the modulation of pain-like behavior in awake animals using a mouse model of inflammatory bladder pain. These experiments will not only help determine the extent of CGRP in the differential processing of bladder pain by the left and right central amygdala but also provide a better understanding of a contributing mechanism to UCPP and therefore open the door for more advanced and effective CNS targeted therapies for patients.