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: 10399656
• 负责人: BENEDICT J KOLBER
• 金额: $ 34.43万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-18 至 2023-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399656
• 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; Persons; 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 pain management; chronic pelvic pain; clinically relevant; effective therapy; gray matter; human model; insight; male; men; new therapeutic target; novel; novel therapeutic intervention; optogenetics; pain patient; parabrachial nucleus; pituitary adenylate cyclase activating polypeptide; prevent; protein expression; response; trait; urologic; urologic chronic pelvic pain syndrome; 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.

项目摘要 泌尿科慢性骨盆疼痛（UCPP）综合征，通常被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/慢性骨盆疼痛综合征（CP/CPP），代表最大的 慢性内脏疼痛障碍的常见类型。尽管内脏的外围输入失调 可能解释了疾病的许多症状，无法理解和治疗中枢神经 系统（CNS）的变化可能阻止受影响患者的完全康复。我们实验室的长期目标是 了解大脑中的区域负责开发和维护的程度 持续的疼痛和泌尿科条件中存在的情感障碍。我们的目标 发现并开发新的CNS治疗范例，以补充针对的方法 膀胱。最近的证据表明，中枢神经系统中的中央杏仁核可能是一个重要的基因座 对于内脏疼痛与焦虑之间的相互作用 UCPP。通过确定杏仁核在膀胱疼痛的动物模型中的作用，将提供洞察力 人类状况的潜在生理学。来自人类和动物模型的证据表明 左右杏仁核可能会差异调节疼痛。左右半球激活的方差 在人类语言生产，视觉处理和复杂的计划任务中得到很好的描述。 [功能 在包括杏仁核在内的大脑的情感处理区域中存在横向化 包括右脑充当压力和损伤的反应中心，包括鸟类和哺乳动物。这 保护表明，边缘电路的横向化可能是进化上重要的现象。] 偏侧化失调可能也可能在疾病中起重要作用的想法是一个新颖的概念 重要的临床相关性。 UCPP患者显示杏仁核灰质的侧向变化和侧向 杏仁核与中枢神经系统其他区域的功能连接。负责传入的分子介质 左侧与右杏仁核的信息仍然未知。该提议的目的是确定 左和右中央杏仁核与分子之间的膀胱疼痛侧向 负责这种现象的机制。这个目标将通过两个截然不同的实现，但 互补的特定目的。在本提案的目标1中，我们将确定左右杏仁核的程度 刺激对照或敏化膀胱后激活，同时还探测大脑的区域 通过其伤害性信息传播。在AIM 2中，我们将操纵特定的脑干投影 杏仁核以确定哪些细胞在两个对照中都足以且必要 和敏化条件。总体而言，该建议将有助于确定杏仁核的程度和机制 疼痛刺激刺激过程中的激活以及过度活跃的杏仁核的机制 如UCPP所示，会导致膀胱疼痛。