Impact of amygdala lateralization on processing and modulation of bladder pain

杏仁核偏侧化对膀胱疼痛处理和调节的影响

• 批准号: 9985661
• 负责人: BENEDICT J KOLBER
• 金额: $ 4.24万
• 依托单位: DUQUESNE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9985661
• 关键词: Affect; Affective; Amygdaloid structure; Anatomy; Animal Model; Animals; Anxiety; Area; Behavior; Behavioral; Bilateral; Birds; Bladder; Brain; Brain Stem; Brain region; Calcitonin Gene-Related Peptide; Cell Nucleus; Cells; Chronic; Chronic Prostatitis; Clinical Pathways; Clinical Treatment; Cognitive; Complement; Complex; Cyclophosphamide; Data; Development; Diagnosis; Disease; Emotional; Emotions; Failure; Female; Functional disorder; Goals; Human; Inflammation; Injury; Interstitial Cystitis; Language; Learning; Left; Maintenance; Mammals; Measures; Mediator of activation protein; Modeling; Molecular; Mus; Neuraxis; Neurons; Neuropeptides; Nociception; Organ; Outcome; Output; Pain; Pain Disorder; Pathway interactions; Patients; Pelvic Pain; Peripheral; Persistent pain; Physiology; Play; Population; Population Projection; Production; Quality of life; Recovery; Role; Signal Transduction; Stress; Structure; Symptoms; Syndrome; Travel; Viscera; Visceral; Visceral pain; Woman; Work; affective disturbance; behavioral response; bladder pain; cell type; chronic pain; chronic pelvic pain; clinically relevant; effective therapy; gray matter; human model; insight; male; men; new therapeutic target; novel; novel therapeutics; optogenetics; pain patient; parabrachial nucleus; pituitary adenylate cyclase activating polypeptide; prevent; protein expression; response; trait; urologic; visual processing

PROJECT SUMMARY Urologic chronic pelvic pain (UCPP) syndromes, commonly diagnosed as interstitial cystitis/bladder pain syndrome (IC/BPS) or chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), represent the most common type of chronic visceral pain disorders. Although dysregulation of peripheral inputs from the viscera likely account for a number of the symptoms of the diseases, a failure to understand and treat central nervous system (CNS) changes likely prevents complete recovery for affected patients. The long-term goal of our lab is to understand the extent to which areas in the brain are responsible for the development and maintenance of persistent pain and accompanying affective disturbances that exist within urologic conditions. We aim to discover and develop novel CNS treatment paradigms for this disease to complement approaches directed at the bladder. Recent evidence has suggested that the central amygdala in the CNS may be an important locus for the interaction between visceral pain and anxiety, potentially serving as a driver for chronic conditions like UCPP. By determining the role of the amygdala in animal models of bladder pain, insight will be provided into the underlying physiology of the human condition. Evidence from human and animal models has shown that the left and right amygdala may differentially regulate pain. Variances in left and right hemisphere activation are well described in human language production, visual processing, and complex planning tasks. [Functional lateralization exists in emotional processing areas of the brain, including the amygdala, across multiple taxa including birds and mammals where the right brain serves as a reactive center to stress and injury. This conservation suggests that lateralization of limbic circuits is likely an evolutionarily important phenomenon.] The idea that dysregulation in lateralization might also play a significant role in disease is a novel concept with important clinical relevance. UCPP patients show lateralized changes in amygdala gray matter and lateralized amygdala functional connectivity to other areas in the CNS. The molecular mediators responsible for incoming information to the left versus right amygdala remain unknown. The objective of this proposal is to determine the extent of bladder pain lateralization between the left and right central amygdalae and the molecular mechanisms responsible for this phenomenon. This objective will be met through two distinct but complementary specific aims. In Aim 1 of this proposal, we will determine the extent of left and right amygdala activation following stimulation of control or sensitized bladders, while also probing the areas of the brain through which nociceptive information travels. In Aim 2, we will manipulate specific brainstem projections to the amygdala to determine which cells are sufficient and necessary for lateralized pain-like output in both control and sensitized conditions. Overall, this proposal will help determine the extent and mechanisms of amygdala activation during painful bladder stimulation and the mechanisms by which an overactive amygdala may contribute to bladder pain as seen in UCPP.

项目概要 泌尿科慢性盆腔疼痛 (UCPP) 综合征，通常诊断为间质性膀胱炎/膀胱疼痛 综合征（IC/BPS）或慢性前列腺炎/慢性盆腔疼痛综合征（CP/CPPS），代表最 常见类型的慢性内脏疼痛疾病。尽管来自内脏的外周输入失调 未能理解和治疗中枢神经系统可能是这些疾病的许多症状的原因 系统（CNS）的变化可能会阻碍受影响患者的完全康复。我们实验室的长期目标是 了解大脑中哪些区域负责发育和维持 泌尿科疾病中存在的持续性疼痛和伴随的情感障碍。我们的目标是 发现和开发针对这种疾病的新的中枢神经系统治疗范例，以补充针对该疾病的方法 膀胱。最近的证据表明中枢神经系统的中央杏仁核可能是一个重要的部位 内脏疼痛和焦虑之间的相互作用，可能是慢性疾病的驱动因素，例如 UCPP。通过确定杏仁核在膀胱疼痛动物模型中的作用，将深入了解 人类状况的基本生理学。来自人类和动物模型的证据表明 左右杏仁核可能对疼痛有不同的调节作用。左右半球激活的差异 在人类语言产生、视觉处理和复杂的规划任务中都有很好的描述。 [功能性 偏侧化存在于大脑的情绪处理区域，包括杏仁核，跨多个类群 包括鸟类和哺乳动物，它们的右脑是压力和伤害的反应中心。这 保守性表明边缘回路的侧化可能是一种进化上重要的现象。] 侧化失调也可能在疾病中发挥重要作用，这是一个新概念， 重要的临床相关性。 UCPP 患者表现出杏仁核灰质的单侧变化和单侧化 杏仁核与中枢神经系统其他区域的功能连接。负责传入的分子介体 左右杏仁核的信息仍然未知。该提案的目的是确定 左、右中央杏仁核之间的膀胱疼痛偏侧化程度和分子 造成这种现象的机制。这一目标将通过两个不同但 互补的具体目标。在该提案的目标 1 中，我们将确定左右杏仁核的范围 刺激控制或敏感膀胱后激活，同时还探测大脑区域 伤害性信息通过它传播。在目标 2 中，我们将操纵特定的脑干投射到 杏仁核确定哪些细胞对于两侧控制中的偏侧疼痛样输出是充分和必要的 和敏感条件。总体而言，该提案将有助于确定杏仁核的范围和机制 疼痛性膀胱刺激期间的激活以及过度活跃的杏仁核可能的机制 导致 UCPP 中出现的膀胱疼痛。