The impact of amygdala CGRP receptors on the development of persistent bladder pain.

项目摘要 泌尿系统慢性盆腔疼痛综合征（UCPPS）影响着全世界数百万人，目前 治疗由于缺乏功效而受到限制。虽然发展的基本机制 和维持内脏疼痛的机制知之甚少，内脏疼痛被认为是与大脑回路有关， 可能会导致慢性病。杏仁核中央核（CeA）作为一种重要的神经元，越来越受到人们的关注。 慢性疼痛病理学中的重要区域。人类和啮齿类动物的研究结果显示， 疼痛调制中CeA的半球偏侧化。虽然正确的CeA已被证明会导致疼痛 在躯体和内脏疼痛模型中，已显示左侧CeA减弱内脏膀胱疼痛。最近 有证据表明，CeA神经元的活动不仅是不对称的，而且随着时间的推移而变化， 诱发神经性疼痛。然而，尚不清楚CeA的时间依赖性激活是否普遍存在 持续性膀胱疼痛我的目的是进一步探讨大脑中动脉的半球和时间的变化， 膀胱致敏和损伤的背景，以及确定可能负责驾驶的细胞类型 这些变化。降钙素基因相关肽（CGRP）是一种神经肽，已被证明可产生 CeA内的不同不对称功能。在躯体疼痛中，CGRP已被证明具有 左侧CeA具有抗伤害感受功能，右侧具有原伤害感受功能。然而， 在膀胱疼痛模型中，CGRP和CGRP受体在大脑中的作用。的总体目标 该建议是确定CGRP受体随时间对膀胱疼痛相关的偏侧化的影响。我 将通过以下方式实现这一目标：1）确定CGRP受体阳性神经元（位于右侧或左侧CeA） 可能影响两种持续性膀胱疼痛模型的疼痛样行为; 2）研究CGRP的CeA活性 在清醒行为的小鼠中，来自左侧或右侧臂旁核（PBn）的投射细胞。围绕 CGRP受体在内脏痛调制中的作用可以提供对潜在的 有助于CeA内疼痛相关偏侧化的机制。这反过来又会导致 以及膀胱疼痛有效中枢神经系统靶向治疗的进展。

PROJECT SUMMARY Urologic chronic pelvic pain syndrome (UCPPS) affects millions of individuals worldwide, and current treatments are limited due to their lack of efficacy. Although the underlying mechanisms of the development and maintenance of visceral pain are poorly understood, visceral pain is thought to engage brain circuits that may contribute to chronicity. The central nucleus of the amygdala (CeA) has received increasing attention as a significant region in the pathology of chronic pain. Findings from both human and rodent studies have revealed hemispheric lateralization of the CeA in pain modulation. While the right CeA has been shown to drive pain in models of somatic and visceral pain, the left CeA has been shown to attenuate visceral bladder pain. Recent evidence has implicated that CeA neuronal activity is not only asymmetric, but also changes with time once neuropathic pain is induced. However, it is unknown whether time-dependent activation of the CeA is prevalent in persistent bladder pain. I aim to further explore the hemispheric and temporal changes of the CeA in the context of bladder sensitization and injury, as well as identify cell-types that might be responsible for driving these changes. Calcitonin gene-related peptide (CGRP) is a neuropeptide that has been shown to produce divergent asymmetric functions within the CeA. In somatic pain, CGRP has been shown to have an antinociceptive function in the left CeA and a pronociceptive function in the right. However, little is understood about the role of CGRP and CGRP receptors in the brain in models of bladder pain. The overall objective of this proposal is to determine the influence of CGRP receptors on bladder pain-related lateralization over time. I will approach this goal by: 1) determining how CGRP receptor positive neurons (located in the right or left CeA) may influence pain-like behavior in two persistent bladder pain models, and 2) studying CeA activity of CGRP projection cells from the left or right parabrachial nucleus (PBn) in awake-behaving mice. Focusing on the contributions of CGRP receptors in visceral pain modulation could provide insight into the underlying mechanisms contributing to pain-related lateralization within the CeA. This, in turn, will lead to the development and advancement of effective CNS targeted therapies for bladder pain.