Modulation of protracted opioid withdrawal by dorsal raphe dynorphin neurons

中缝背侧强啡肽神经元对长期阿片类药物戒断的调节

• 批准号: 10505724
• 负责人: Matthew B Pomrenze
• 金额: $ 15.84万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10505724
• 关键词: Abstinence; Address; Advisory Committees; Anhedonia; Award; Behavior; Behavioral; Behavioral Model; Brain; Brain region; COVID-19 pandemic; Chronic; Data; Disease; Dopamine; Dorsal; Dynorphins; Economics; Emotional; Exhibits; Fiber; Genetic; Goals; Human; Impairment; Injections; Knock-out; Knockout Mice; Knowledge; Learning; Maps; Mediating; Mental Depression; Mentors; Mentorship; Modeling; Morphine; Mus; Nerve; Neurons; Neuropeptides; Nucleus Accumbens; Opioid; Overdose; Pathogenesis; Pathway interactions; Phase; Photometry; Population; Procedures; Receptor Activation; Relapse; Research; Rewards; Risk; Role; Self Administration; Serotonin; Social Behavior; Social Controls; Social isolation; Stress; Techniques; Testing; Training; Withdrawal; Withdrawal Symptom; base; behavior test; behavioral impairment; cell type; cost; craving; dopaminergic neuron; dorsal raphe nucleus; drug withdrawal; emotional symptom; improved; in vivo; insight; kappa opioid receptors; monoamine; mouse model; neural circuit; neurochemistry; neuromechanism; opioid epidemic; opioid overdose; opioid use; opioid use disorder; opioid withdrawal; optogenetics; overdose death; pre-clinical; preference; prevent; programs; receptor expression; relapse risk; remifentanil; reward circuitry; sensor; social; social deficits; therapeutic development; tool

Project summary Opioid use disorder (OUD) is a chronic relapsing disorder that has cost the U.S. more than $1 trillion in 2017 alone. While initially driven by brain reward circuits, opioid consumption increasingly engages stress-related neural circuits that drive maladaptive emotional states. During the abstinent weeks, months, and years following opioid use, the risk of relapse is increased by emotional symptoms, such as social avoidance, depression, and opioid cravings. Similarly, tendencies to self-isolate during periods of protracted opioid withdrawal increase the risk of lethal overdose. The rapid escalation of opioid overdoses in the U.S. reflects the need for more data on neural mechanisms underlying protracted opioid withdrawal. The neuropeptide dynorphin and kappa opioid receptors (KOR) contribute to stress, aversion, and behavioral consequences of withdrawal. While evidence suggests that KOR effects may be due to modulation of dopamine and serotonin release in the nucleus accumbens (NAc), the brain regions and neural mechanisms mediating KOR control of opioid withdrawal remain a critical gap in knowledge. In this K99/R00 pathway to independence award, I aim to identify mechanisms by which KORs mediate changes in behavior during withdrawal. Using a mouse model of chronic, non-contingent morphine exposure, I have collected preliminary data indicating that 1) KOR activity in the NAc controls social avoidance and anhedonia produced during protracted withdrawal and 2) a population of dynorphin-producing neurons in the dorsal raphe nucleus, but not dynorphin neurons in the NAc itself, mediate the same effects. During the mentored phase, in Aim 1, I will learn to perform in vivo optogenetic procedures and fiber photometry recordings to characterize the role of dorsal raphe dynorphin neuron projections to the NAc in withdrawal behaviors. In Aim 2, I will expand on the model of non-contingent injections and establish a new model of remifentanil self-administration and examine relapse behavior during protracted withdrawal. I will also test changes in social and depression-like behaviors after self-administration. In the independent phase, in Aim 3, I will use my training from the K99 phase to combine optogenetics and fiber photometry recordings of dorsal raphe dynorphin inputs to the NAc with remifentanil self-administration and relapse testing. In Aim 4, I will expand on additional preliminary data collected with non-contingent injections showing that KOR expression in serotonin and dopamine neurons is critical for social avoidance and depression-like behaviors, respectively. I will use fiber photometry and fluorescent sensors of dopamine and serotonin to record release in the NAc during protracted withdrawal testing. In addition, I will examine dopamine and serotonin dynamics in the self-administration model developed in Aim 2 by testing mice with the same cell-type specific KOR knockouts and performing photometry recordings of release in the NAc. Overall, this proposal will investigate key mechanisms underlying protracted opioid withdrawal with a combination of advanced techniques, while simultaneously providing me with the tools necessary for establishing an independent research program aimed at dissecting the pathogenesis of OUD.

项目摘要 阿片类药物使用障碍（OUD）是一种慢性复发障碍，在2017年使美国损失超过1万亿美元 独自的。虽然最初是由大脑奖励电路驱动的，但阿片类药物的消费越来越多地与压力有关 驱动不良适应情绪状态的神经回路。在避免的几周，几个月和几年之后 阿片类药物的使用，情绪症状（例如社会避免，抑郁和抑郁症）增加了复发的风险 阿片类药物的渴望。同样，在旷日持久的阿片类药物戒断期间自我分离的趋势增加了 致命过量的风险。在美国，阿片类药物过量的快速升级反映了对更多数据的需求 神经机制是旷日持久的阿片类药物戒断。神经肽Dynorphin和Kappa阿片类药物 受体（Kor）有助于压力，厌恶和行为后果。同时证据 表明KOR效应可能是由于多巴胺和5-羟色胺在细胞核中的调节所致 伏隔（NAC），介导kor控制阿片类药物戒断的大脑区域和神经机制仍然存在 知识的关键差距。在这项K99/R00独立奖中，我旨在确定机制 Kors介导退出期间行为的变化。使用慢性，非束缚的鼠标模型 吗啡暴露，我收集了初步数据，表明1）NAC中的KOR活动控制社交 避免戒断期间产生的避免和抗甲曲，2）产生大酚的人群 背侧raphe核中的神经元，而不是NAC本身中的dynorphin神经元，介导了相同的作用。 在指导阶段，在AIM 1中，我将学习执行体内光学遗传过程和光纤光度法 录音以表征背心dynorphin神经元对NAC的作用的作用 行为。在AIM 2中，我将扩展非注射的模型，并建立一个新的模型 雷替丹尼在长期戒断过程中自我管理并检查复发行为。我也会测试 自我管理后社会和抑郁症行为的变化。在独立阶段，在AIM 3中，我 将使用我从K99阶段的培训来结合背raphe的光遗传学和光纤光度计记录 通过Remifentanil自我给药和复发测试向NAC输入Dynorphin。在AIM 4中，我将扩展 用非刺射注射收集的其他初步数据，显示kor在5-羟色胺中的表达 多巴胺神经元分别对社会回避和抑郁症般的行为至关重要。我将使用纤维 多巴胺和5-羟色胺的光度法和荧光传感器在持久期间记录NAC中的释放 提取测试。此外，我将在自我管理模型中检查多巴胺和5-羟色胺动力学 通过用相同的细胞类型特异性KON敲除和执行光度法测试小鼠在AIM 2中开发 NAC中发行的录音。总体而言，该提案将调查持久的关键机制 阿片类药物与高级技术的结合，同时为我提供工具 建立旨在解剖OUD发病机理的独立研究计划所必需的。