ACC Sensitization in Visceral Hypersensitive Rats

内脏过敏大鼠的 ACC 致敏作用

• 批准号: 7168205
• 负责人: YING LI
• 金额: $ 33.1万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-15 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7168205
• 关键词: Acetic Acid; Acetic Acids; Affective; Albumins; Anaphylaxis; Anterior; Area; Brain; Colorectal; Condition; Cutaneous; Disease; Etiology; Event; Fire - disasters; Glutamate Receptor; Glutamates; Human; Hypersensitivity; Image; Irritable Bowel Syndrome; Lead; Learning; Long-Term Depression; Long-Term Potentiation; Medial; Mediating; Mediation; Memory; Microdialysis; Modeling; Motor; N-Methylaspartate; Nerve; Neural Pathways; Neuronal Plasticity; Neurons; Nociception; Pain; Pain Threshold; Patients; Pelvis; Perception; Persons; Pharmaceutical Preparations; Process; Property; Public Health; Rattus; Role; Sensory; Signal Transduction; Splanchnic Nerves; Stimulus; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Thalamic Nuclei; Visceral; Visceral Afferents; avoidance behavior; calmodulin-dependent protein kinase II; cingulate cortex; colorectal distension; design; egg; gamma-Aminobutyric Acid; irritation; neuronal excitability; response; transmission process

DESCRIPTION (provided by applicant): Visceral hypersensitivity is common among patients with irritable bowel syndrome (IBS). The anterior cingulate cortex (ACC) is a brain center which mediates affective responses to pain and gut motor function. Imaging of the human brain indicates abnormal processing of visceral sensory signals by the ACC in IBS patients, however the mechanism is unknown. The current proposal is designed to characterize the electrophysiological properties of ACC neurons, and to explore the synaptic plasticity following the induction of visceral hypersensitivity. We hypothesize that persistence of a heightened tonic visceral afferent nociceptive input to the ACC induces ACC neuronal plasticity characterized by an increase in synaptic transmission. The sensitization of ACC neurons may occur as a result of alteration of activity-dependent plasticity (long-term potentiation, LTP and long-term depression, LTD). This heightened synaptic transmission leads to a reduction in pain threshold and an amplification of affective responses to pain. To test this hypothesis, we plan to use two visceral hypersensitive rat models: colonic anaphylaxis (egg albumin) and colorectal irritation (acetic acid). Electrophysiological recording of single ACC neuronal spike firing in response to colorectal distension will be combined with reversal microdialysis to directly infuse drugs to the dendritic area of neurons to demonstrate the enhancement of synaptic glutamatergic transmission in the ACC. We will record the local field potential and characterize the facilitation of LTP and loss of LTD, a key synaptic mechanism of cortical plasticity, following initiation of visceral hypersensitivity. The mechanisms and intracellular signal events underlying the enhanced ACC neuronal excitability and synaptic plasticity will be explored. Finally, we will characterize the role of ACC in pain-related affective processing and elucidate the cellular mechanisms in the induction of learning and memory in ACC neurons. Understanding the processes that lead to ACC neuronal plasticity and its consequences in pain anticipation that precedes avoidance behavior may prove vital to our understanding of the etiology and treatment of CNS abnormalities associated with visceral hypersensitivity. Relevance to public health: Patients with functional Gl disorders commonly demonstrate visceral hypersensitivity. This study seeks to understand the causes and provide clues for the treatment of this condition.

描述（由申请人提供）：内脏过敏在肠易激综合征（IBS）患者中很常见。前扣带皮层（ACC）是一个大脑中心，介导对疼痛和肠道运动功能的情感反应。人脑成像显示IBS患者的ACC处理内脏感觉信号异常，但其机制尚不清楚。本研究旨在描述ACC神经元的电生理特性，并探索内脏超敏反应诱导后的突触可塑性。我们假设，持续增强的强直性内脏传入伤害性输入ACC诱导ACC神经元可塑性，其特征是突触传递增加。ACC神经元的敏化可能是活动依赖性可塑性改变的结果（长期增强，LTP和长期抑制，LTD）。这种增强的突触传递导致疼痛阈值的降低和对疼痛的情感反应的放大。为了验证这一假设，我们计划使用两种内脏过敏大鼠模型：结肠过敏反应（鸡蛋白蛋白）和结肠刺激（醋酸）。电生理记录单个ACC神经元对结直肠膨胀反应的尖峰放电将结合逆转微透析，直接将药物注入神经元的树突区域，以证明ACC突触谷氨酸能传递的增强。我们将记录局部场电位，并描述LTP的促进和LTD的丧失，这是内脏超敏反应开始后皮层可塑性的关键突触机制。ACC神经元兴奋性和突触可塑性增强的机制和胞内信号事件将被探讨。最后，我们将描述ACC在疼痛相关情感加工中的作用，并阐明ACC神经元诱导学习和记忆的细胞机制。了解导致ACC神经元可塑性的过程及其在避免行为之前的疼痛预期中的后果可能对我们理解与内脏超敏反应相关的中枢神经系统异常的病因和治疗至关重要。与公共卫生相关：功能性Gl紊乱患者通常表现为内脏过敏。这项研究旨在了解其原因，并为治疗这种疾病提供线索。