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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要丘脑室旁核（PVT）是上行伤害感受之间的关键节点 PVT 的病变、化学遗传学和光遗传学抑制减少。研究表明，NAc 投射的 PVT 神经元具有动物完成目标导向行为的能力。对于调节阿片类药物依赖或阿片类药物使用障碍是必要的。依赖性，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回避行为为特征的依赖性 PVT 富含所有 4 种阿片受体，尤其是 mu-阿片受体 (MOR)——吗啡和芬太尼等镇痛药物的主要目标。立即早期基因 c-fos 的积极的、活动驱动的表达表明鉴于越来越多的证据表明 PVT 参与了阿片类药物戒断反应。阿片类药物依赖的表达，我将检查急性和慢性阿片类药物给药对 PVT 的影响因此，目标 1 致力于表征阿片类药物对 MOR 的急性作用。 PVT 突触后以及磷酸化在 PVT 急性脱敏过程中的作用。 MOR C 末端位点的磷酸化会导致急性脱敏的诱导，即被认为是长期耐受性发展或减弱的先兆。后脑区域（例如蓝斑（LC））的反应性已得到很好的描述，但较少被描述自从 MOR 磷酸化以来，人们就知道耐受性如何塑造介导目标导向行为的回路。被认为是耐受性发展的第一步，我在 PVT 的连续工作将决定导致多种阿片类药物戒断的长期适应，包括： PVT 中的吗啡、芬丁醛和丁诺啡以及 MOR (+) 输入的突触前适应； PVT 的总体目标是描述慢性 PVT 后 MOR 的适应情况。此外，这项工作是我在科学上实现目标并带来的基础。在我的博士后奖学金目标 2 中，我建议寻找一位具有情绪专业知识的博士后导师。疾病、慢性压力和/或成瘾者可以利用我的电生理学专业知识并培训我体内成像和行为分析的严格实验设计和数据分析。术语目标是建立从分子角度剖析电路所需的技能，并遵循这些适应来唤醒该提案旨在解决 BRAIN Initiative 的科学审查和高优先级问题。我的电生理学基础将是使用多模式方法监测神经活动的研究领域。很好地应对从两个完整的神经网络记录动态神经活动的挑战和单细胞；以分子精度告诉我们动态网络。