Mechanistic description of tolerance/withdrawal from opioids in the paraventricular nucleus of the thalamus

丘脑室旁核阿片类药物耐受/戒断的机制描述

• 批准号: 10813734
• 负责人: Omar Koita
• 金额: $ 4.77万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10813734
• 关键词: ADRBK1 gene; Acute; Acute Pain; Address; Amygdaloid structure; Analgesics; Animals; Anterior; Area; Awareness; BRAIN initiative; Behavior; Behavioral Assay; Brain; Cells; Chronic; Chronic stress; Clinical; Closure by clamp; Communication; Communities; Complex; Dangerousness; Data Analyses; Dedications; Dependence; Development; Disease; Disparity; Electric Stimulation; Electrophysiology (science); Emotions; Environment; Experimental Designs; FOS gene; Fellowship; Fentanyl; Foundations; Funding; Future; Generations; Genetic; Genetic Identity; Goals; Grant; Hydrocodone; Hyperalgesia; Image; Immediate-Early Genes; Interview; Knowledge; Label; Lead; Lesion; Link; Manuscripts; Mediating; Mentors; Mentorship; Methods; Molecular; Monitor; Mood Disorders; Morphine; Morphology; Motivation; Naloxone; Neurons; Neurosciences; Nociception; Nucleus Accumbens; ORL1 receptor; Opiate Addiction; Opioid; Opioid Receptor; Oxycodone; Pattern; Peer Review; Pharmaceutical Preparations; Phosphorylation; Phosphorylation Site; Physical Dependence; Play; Postdoctoral Fellow; Potassium; Presynaptic Receptors; Process; Property; Publications; Receptor Signaling; Research; Research Priority; Research Project Grants; Rewards; Risk; Role; Science; Scientist; Services; Shapes; Slice; Structure of paraventricular nucleus of thalamus; Students; Synapses; Synaptic plasticity; Technical Expertise; Techniques; Thalamic structure; Therapeutic; Therapeutic Effect; Thinness; Training; Universities; Withdrawal; Withdrawal Symptom; Work; Writing; addiction; avoidance behavior; awake; career; career development; channel blockers; chronic pain; collaborative approach; craving; desensitization; diversity and inclusion; drug seeking behavior; hindbrain; in vivo imaging; inhibitor; innovation; insight; locus ceruleus structure; motivated behavior; mu opioid receptors; multimodality; neural; neural network; neuronal circuitry; opioid exposure; opioid overdose; opioid use; opioid use disorder; opioid withdrawal; optogenetics; overdose death; pandemic disease; peer; postsynaptic; prescription opioid; presynaptic; receptor; response; side effect; skills; standard care; symposium; therapeutic opioid; tool; two-photon; underserved community; voltage clamp

Project Summary The paraventricular nucleus of the thalamus (PVT) is a critical node between ascending nociceptive information and goal directed behavior. Lesions, chemogenetic and optogenetic inhibition of the PVT reduces an animal’s ability to complete goal-directed behaviors. Studies have suggested NAc-projecting PVT neurons are necessary for mediating opioid dependence, or opioid use disorder. Chronic opiate use induces opioid dependence, a complex disease whose components including tolerance, drug seeking or craving, and physical dependence characterized by withdrawal avoidance behavior. The PVT is rich with all 4 opioid receptors, particularly the mu-opioid receptor (MOR) – the primary target of analgesic drugs like morphine and fentanyl. Interestingly, activity-driven expression of the immediate early gene c-fos indicates increased excitation of the PVT in response to opioid withdrawal. Given the growing body of evidence that the PVT is involved in the expression of opioid dependence, I will examine the effects of acute and chronic opioid administration on PVT neurons. Thus, Aim 1 is dedicated to characterizing the acute actions of opioids on MORs pre- and postsynaptic to the PVT and the role of phosphorylation in the process of acute desensitization in the PVT. Phosphorylation of sites on the C-terminus of MORs results in the induction of acute desensitization which is thought to be a precursor for the development of long-term tolerance. Tolerance, or a diminished responsiveness has been well described in hindbrain regions such as the locus coeruleus (LC) yet less is known about how tolerance shapes circuits that mediate goal directed behavior. Since phosphorylation of MOR is thought to be the initial step in the development of tolerance, I have characterized these mechanisms in the PVT. Sequential work will determine long-term adaptations that lead to withdrawal to multiple opioids including, morphine, fentynal, and bupinorphine in the PVT; as well as presynaptic adaptations of MOR (+) inputs to the PVT. The overall goal of this proposal is to characterize the adaptations of MORs in PVTs seen after chronic opioid treatment. Additionally, this work stands as the foundation of what I aim to achieve in science and bring to my post-doctoral fellowship. In Aim 2, I propose to identify a post-doctoral mentor with expertise in mood disorders, chronic stress, and/or addiction who can utilize my electrophysiology expertise and train me in rigorous experimental design and data analysis for in-vivo imaging and behavioral assays. The broad, long term goal is to build the skill set required to dissect a circuit molecularly and follow these adaptations to awake and moving animals. This proposal seeks to address the BRAIN Initiative’s Scientific Review and High Priority Research Area for using multimodal methods to monitor neural activity. My electrophysiological foundation will serve well to seize the challenge of recording dynamic neuronal activity from both complete neural networks and single cells; informing us about dynamic networks with molecular precision.

项目摘要 丘脑室旁核（PVT）是一个关键节点之间的上升伤害性 信息和目标导向行为。PVT的病变、化学遗传学和光遗传学抑制减少 动物完成目标导向行为的能力。研究表明，投射NAC的PVT神经元 是调节阿片类药物依赖或阿片类药物使用障碍所必需的。慢性阿片类药物使用诱导阿片类药物 依赖是一种复杂的疾病，其组成部分包括耐受性，药物寻求或渴望，以及身体 以逃避行为为特征的依赖。PVT富含所有4种阿片受体， 特别是μ-阿片受体（莫尔）-镇痛药如吗啡和芬太尼的主要靶点。 有趣的是，立即早期基因c-fos的活动驱动表达表明， 对阿片类药物戒断反应的PVT。鉴于越来越多的证据表明，PVT参与了 表达阿片类药物依赖，我将检查急性和慢性阿片类药物给药对PVT的影响 神经元因此，目标1致力于表征阿片类药物对MORs的急性作用， 本研究旨在探讨突触后神经元对PVT的作用以及磷酸化在PVT急性脱敏过程中的作用。 MORs C-末端位点的磷酸化导致急性脱敏的诱导， 被认为是长期耐受性发展的前兆。容忍度，或减少 反应性在后脑区域如蓝斑（LC）得到了很好的描述，但很少被 了解容忍度如何塑造介导目标导向行为的回路。由于莫尔的磷酸化 被认为是耐受性发展的第一步，我已经描述了这些机制， Pvt.连续的工作将确定长期的适应，导致退出多种阿片类药物，包括， PVT中的吗啡、芬太尼和丁丙诺啡;以及莫尔（+）输入对PVT的突触前适应。 Pvt.本提案的总体目标是描述慢性肺栓塞后PVTs中MORs的适应性。 阿片类药物治疗此外，这项工作是我在科学领域实现目标的基础， 我的博士后奖学金在目标2中，我建议确定一位在情绪方面具有专业知识的博士后导师 疾病，慢性压力和/或成瘾，谁可以利用我的电生理学专业知识，并训练我在 用于体内成像和行为测定的严格实验设计和数据分析。宽，长 学期目标是建立所需的技能，以分子方式剖析电路，并遵循这些适应性来唤醒 移动的动物。该提案旨在解决BRAIN倡议的科学审查和高优先级 使用多模态方法监测神经活动的研究领域。我的电生理学基础 很好地抓住了从两个完整的神经网络记录动态神经元活动的挑战， 和单细胞;告诉我们动态网络的分子精度。