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

中央杏仁核中细胞类型对膀胱疼痛调节的特异性贡献的研究

• 批准号: 9760073
• 负责人: Heather Noel Allen
• 金额: $ 4.22万
• 依托单位: DUQUESNE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-19 至 2022-01-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760073
• 关键词: Abdomen; Affect; Affective; Amygdaloid structure; Anatomy; Animals; Arthritis; Automobile Driving; Behavior; Behavioral; Bilateral; Bladder; Brain; Brain Stem; Calcitonin Gene-Related Peptide; Calcitonin-Gene Related Peptide Receptor; Cell Nucleus; Cells; Chronic; Coupled; Data; Development; Diagnosis; Disease; Emotional; Emotional Disturbance; Exhibits; Failure; Frequencies; Goals; Human; Image; Inflammatory; Infusion procedures; Investigation; Knowledge; Left; Magnetic Resonance Imaging; Maintenance; Measurement; Mechanics; Microinjections; Molecular; Mus; Neuraxis; Neurons; Neuropeptides; Nociception; Output; Pain; Pathology; Patients; Pharmacology; Physiological; Quality of life; Research; Rodent Model; Role; System; Testing; Therapeutic; Therapeutic Intervention; Time; Treatment Efficacy; United States; Urination; Visceral; Visceral pain; Work; awake; behavioral response; bladder pain; cell type; chronic pain; chronic painful condition; chronic pelvic pain; effective therapy; experimental study; human model; improved; intense pain; mouse model; novel; optogenetics; pain patient; pain processing; parabrachial nucleus; preference; response; targeted treatment; urologic

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.

项目概要 泌尿科慢性盆腔疼痛 (UCPP) 综合征是最常见的慢性内脏疼痛病症， 影响美国 5 至 1000 万人。 UCPP缺乏有效的治疗方法 部分原因可能是由于未能理解中枢神经系统对调节的贡献 疾病。最近的证据表明杏仁核的中央核是大脑中的一个重要区域。 膀胱疼痛的病理学。来自人类和啮齿动物模型的证据表明，左、右 杏仁核对疼痛的调节有不同的贡献。 UCPP 患者表现出单侧变化 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 状况。最近，右、左中央杏仁核已被证明在以下方面具有不同的功能： 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 神经肽已分别被证明在中枢具有促伤害感受和抗伤害感受功能 杏仁核。我们的初步数据表明，CGRP 活性在以下情况下表现出有趣的不对称性： 膀胱疼痛，右中央杏仁核中的 CGRP 驱动膀胱疼痛，但左中央杏仁核中的 CGRP 驱动膀胱疼痛 杏仁核阻塞膀胱疼痛。该提案的目标是了解 CGRP 如何为 左和/或右中央杏仁核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) 探索脑干杏仁核中表达 CGRP 的投射对生理的影响 对膀胱刺激的反应，2) 研究这些相同的 CGRP 细胞对膀胱刺激的贡献 使用炎症性膀胱疼痛的小鼠模型调节清醒动物的疼痛样行为。这些 实验不仅有助于确定 CGRP 在膀胱疼痛差异处理中的程度 左、右中央杏仁核，还提供了对促进机制的更好理解 因此，UCPP 为患者提供更先进、更有效的中枢神经系统靶向治疗打开了大门。