ACC Sensitization in Visceral Hypersensitive Rats

内脏过敏大鼠的 ACC 致敏作用

• 批准号: 7342507
• 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/7342507
• 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

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.

内脏超敏反应在肠易激综合征（IBS）患者中很常见。前 扣带皮层（ACC）是介导对疼痛的情感反应和肠道运动功能的脑中心。 人脑成像显示IBS患者ACC对内脏感觉信号的异常处理 患者，但机制不明。目前的提案旨在描述 ACC神经元的电生理特性，并探讨诱导后的突触可塑性 内脏过敏症我们假设持续的高强度内脏传入 ACC的伤害性输入诱导ACC神经元的可塑性，其特征在于突触的增加， 传输ACC神经元的致敏作用可能是由于活动依赖性的 可塑性（长时程增强、LTP和长时程抑制）。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。到 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）和结肠直肠刺激（乙酸）。单个ACC神经元放电的电生理记录 响应于结直肠扩张的放电将与反向微透析结合以直接输注药物 神经元的树突状区域，以证明突触传递的增强， 我们将记录局部场电位并表征LTP的促进和LTD的损失， 内脏高敏感性启动后皮质可塑性的关键突触机制。的机制 和细胞内信号事件的增强ACC神经元兴奋性和突触可塑性将 被探索。最后，我们将描述ACC在疼痛相关的情感处理中的作用，并阐明 ACC神经元诱导学习记忆的细胞机制。了解 导致ACC神经元可塑性的过程及其在疼痛预期中的后果， 回避行为可能对我们理解中枢神经系统异常的病因和治疗至关重要 与内脏高敏感性有关与公共卫生的相关性：功能性GI疾病患者 通常表现出内脏高敏感性。这项研究旨在了解原因，并提供 治疗这种疾病的线索