Contribution of MCL memory circuits to opioid seeking in chronic pain

MCL 记忆回路对慢性疼痛中阿片类药物寻求的贡献

• 批准号: 10198887
• 负责人: Jelena Radulovic
• 金额: $ 28.44万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198887
• 关键词: Abstinence; Affect; Behavior; Brain; Cellular Structures; Cessation of life; Chronic Disease; Computer Models; Data; Development; Dorsal; Drug abuse; Enterobacteria phage P1 Cre recombinase; Face; Female; Genetic Transcription; Glutamates; Goals; Hippocampus (Brain); Human; Image; Individual; Memory; Modeling; Molecular; Molecular Analysis; Morphine; Mus; Neurons; Neurotransmitters; Nucleus Accumbens; Opiate Addiction; Opioid; Pain; Pathway interactions; Patients; Pharmaceutical Preparations; Pilot Projects; Play; Population; Predisposition; Process; Recurrence; Relapse; Resistance; Rewards; Role; Self Administration; Sex Differences; Specificity; Stimulus; Stress; Synapses; Time; Ventral Tegmental Area; addiction; base; chronic pain; chronic painful condition; conditioned place preference; craving; design; drug seeking behavior; experimental study; functional restoration; human data; male; memory process; nerve injury; novel; opioid epidemic; opioid use; optogenetics; pain chronification; pain processing; pain reduction; patient population; prescription opioid; reward processing; sex; spared nerve; success; transmission process

Opioid drugs are widely prescribed to patients suffering from chronic pain despite the fact that we still know very little about the impact of opioids, chronic pain, and both conditions on brain function. The main goals of this project are to (i) provide novel evidence for the functional interaction between reward-, pain-, and memory-processing circuits, (ii) determine how this interaction is affected by chronic pain, and (iii) show whether restoring the function of these circuits can reduce pain and opioid addiction. Based on our recent and pilot studies, we posit that functional changes in projections from the mesolimbic ventral tegmental area (VTA) to DH, carrying information on pain and reward, alter hippocampal plasticity and enable the DH-RSC memory circuit to gain excessive control over both chronic pain and opioid craving. Dissecting the role of individual neurotransmitter circuits is essential for the better understanding of sex-specific differences in opioid seeking, showing higher susceptibility of females to aversive triggers and higher susceptibility of males to rewarding triggers. Specific Aim 1 is designed to determine the role of VTA-DH projections in chronic pain and opioid craving using chemogenetic inactivation of glutamatergic, GABAergic, dopaminergic pathways. Specific Aim 2 will use similar approaches to determine the role of glutamatergic DH-RSC and RSC-VTA projections. Specific Aim 3 will show whether sex-specific activity of discrete VTA-DH-RSC projections is sufficient to induce pain and opioid craving. Specific Aim 4 will integrate key findings of Project 3 with findings of the other projects of the Center by examining the relationship between memory and reward circuits (Project 2), the relationship between transcriptional changes in the VTA and the reorganization of VTA-DH circuits (Project 4), the impact of individual VTA-DH-RSC pathways on whole brain activity and connectivity (Project 1), and the relevance of our findings for patient populations (Project 1). We expect to show that originally distinct pathways processing pain, reward, and memory, alter their stimulus specificity during chronic pain and addiction, causing changes of DH plasticity and reorganization of the VTA-DH-RSC circuit. The circuit, transcriptional, and synaptic mechanisms identified in this project will serve as a basis for development of new treatments for chronic pain and addiction. !

阿片类药物被广泛用于患有慢性疼痛的患者，尽管事实上我们仍然 对于阿片类药物、慢性疼痛以及这两种情况对大脑功能的影响知之甚少。主要 该项目的目标是（i）为奖励、痛苦和 记忆处理电路，(ii) 确定慢性疼痛如何影响这种相互作用，以及 (iii) 显示 恢复这些回路的功能是否可以减轻疼痛和阿片类药物成瘾。根据我们最近和 初步研究中，我们假设中脑边缘腹侧被盖区（VTA）的投影发生功能变化 传递给 DH，携带有关疼痛和奖励的信息，改变海马可塑性并启用 DH-RSC 记忆 电路以获得对慢性疼痛和阿片类药物渴望的过度控制。剖析个人的角色 神经递质回路对于更好地理解阿片类药物寻求中的性别差异至关重要， 显示女性对厌恶触发因素的敏感性更高，而男性对奖励的敏感性更高 触发器。具体目标 1 旨在确定 VTA-DH 预测在慢性疼痛和阿片类药物中的作用 使用谷氨酸能、GABA能、多巴胺能途径的化学遗传学灭活来渴望。具体目标2 将使用类似的方法来确定谷氨酸能 DH-RSC 和 RSC-VTA 预测的作用。 具体目标 3 将显示离散 VTA-DH-RSC 预测的性别特异性活性是否足以 引起疼痛和对阿片类药物的渴望。具体目标 4 将项目 3 的主要发现与其他项目的发现相结合 该中心的项目通过检查记忆和奖励回路之间的关系（项目2）， VTA 转录变化与 VTA-DH 回路重组之间的关系（项目 4）， 个体 VTA-DH-RSC 通路对全脑活动和连接的影响（项目 1），以及 我们的研究结果与患者群体的相关性（项目 1）。我们希望展示出原本截然不同的 处理疼痛、奖励和记忆的通路，在慢性疼痛和过程中改变它们的刺激特异性 成瘾，导致 DH 可塑性变化和 VTA-DH-RSC 回路重组。电路， 该项目中确定的转录和突触机制将作为开发新的基础 治疗慢性疼痛和成瘾。 ！