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

项目摘要 尿路慢性盆腔疼痛(UCPP)综合征是最常见的慢性内脏疼痛症状， 影响到美国500万到1000万人。UCPP缺乏有效的治疗方法是 可能部分是由于未能理解中枢神经系统在调节 疾病。最近的证据表明，杏仁核的中央核是大脑中的重要区域。 膀胱痛的病理学。来自人类和啮齿动物模型的证据表明，左侧和右侧 杏仁核对疼痛的调制有不同的作用。UCPP患者表现出偏侧的变化 杏仁核功能连接性与健康患者和其他内脏疼痛患者的比较 条件。最近，人们发现左右中央杏仁核在大脑中具有不同的功能。 小鼠膀胱疼痛的背景。我们的目标是进一步探索这种偏侧化，以确定分子 负责驱动这些差分功能的调制器。降钙素基因相关肽(CGRP)是一种 神经肽，已被证明在中枢同时具有促伤害和抗伤害感受功能。 杏仁核。我们的初步数据表明，降钙素基因相关肽的活性在 膀胱疼痛，右侧中央杏仁核CGRP驱动膀胱疼痛，左侧中央CGRP驱动膀胱疼痛 杏仁核阻断膀胱疼痛。这项建议的目标是了解CGRP如何对 左侧和/或右侧中央杏仁核对膀胱痛的不同调制。我们将在1)年前实现这一目标 杏仁中央核脑干降钙素基因相关肽投射对生理功能的影响 对膀胱刺激的反应和2)研究这些相同的CGRP细胞在 使用炎症性膀胱痛的小鼠模型对清醒动物的痛样行为进行调节。这些 实验不仅有助于确定CGRP在膀胱痛的不同处理过程中的程度，还将通过 左侧和右侧中央杏仁核也提供了更好的理解 UCPP，从而为患者提供更先进、更有效的中枢神经系统靶向治疗。

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.