Circuit mechanisms for opioid analgesia and addiction in prefrontal cortex

前额皮质阿片类镇痛和成瘾的回路机制

• 批准号: 10607118
• 负责人: Nicole Elise Ochandarena
• 金额: $ 3.92万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607118
• 关键词: Absence of pain sensation; Academic Medical Centers; Acute; Affect; Analgesics; Area; Behavior; Biological Assay; Brain; Calcium; Cells; Chronic; Color; Complex; Corpus striatum structure; Data; Dissociation; Doctor of Philosophy; Drug Prescriptions; Electrophysiology (science); Environment; Future; Genetic; Genetic Suppression; Glutamates; Goals; Histology; Hyperalgesia; Image; Implantable Pump; Interneurons; Knowledge; Mechanics; Medial; Mediating; Medicine; Modeling; Morphine; Motivation; Mus; Naloxone; Nervous System; Neuroanatomy; Neurons; North Carolina; Opiate Addiction; Opioid; Opioid Analgesics; Oral; Output; Oxycodone; Pain; Pain management; Pattern; Pharmaceutical Preparations; Physicians; Population; Postoperative Pain; Prefrontal Cortex; Property; Proxy; Pyramidal Tracts; Receptor Signaling; Relapse; Reporter; Research; Research Proposals; Rewards; Risk; Role; Scientist; Self Administration; Signal Transduction; Testing; Therapeutic; Tissues; Training; United States; Universities; Ventilatory Depression; Withdrawal; addiction; cell type; conditioned place preference; experimental study; hippocampal pyramidal neuron; imaging approach; innovation; mouse model; mu opioid receptors; neural; neural circuit; opioid epidemic; opioid exposure; opioid use; pain behavior; pain relief; programs; receptor expression; receptor function; reward circuitry; single-cell RNA sequencing; skills; subcutaneous

PROJECT SUMMARY (ABSTRACT) The mu opioid receptor (MOR) is widely expressed throughout the nervous system and mediates both analgesic and addictive effects of opioids. Despite the current opioid crisis in the United States, opioid drugs offer unparalleled analgesic efficacy and are prescribed for a variety of pain conditions. To dissociate opioid analgesic and addictive effects, it is essential to determine which neural circuits and cell types mediate each of these effects. MOR signaling in medial prefrontal cortex (mPFC) is of particular significance due to the mPFC function as a key integrative node in ascending and descending pain circuits and its strong connectivity to subcortical reward circuitry. However, how opioids eventually alter the activity of glutamatergic mPFC output neurons to modulate opioid addiction and pain behaviors is unknown. The main outputs of the cortex include two distinct populations of layer 5 glutamatergic projection neurons: intratelencephalic (IT) and pyramidal tract (PT) neurons. IT neurons predominantly project intracortically and to striatum, while PT neurons project broadly and are poised to directly modulate neural activity throughout the brain. Despite evidence supporting a MOR-dependent role for mPFC in pain and addiction, preliminary data suggest that MOR is not expressed directly on IT or PT cells. This project aims to (1) determine how opioid exposure impacts mPFC IT and PT cell activity in mice and (2) delineate the contribution of mPFC IT and PT cells to opioid addiction and analgesia. In order to determine how opioids modulate IT and PT cell activity, dual-color calcium imaging will be used as a proxy for neuronal activity. Neural dynamics of each population will be characterized at baseline, during acute and chronic morphine exposure through subcutaneously implanted pumps, and during naloxone-precipitated withdrawal. To assess the contribution of IT and PT cells to opioid addiction, mPFC IT or PT cell activity will be chemogenetically suppressed in addiction models including morphine conditioned place preference and oxycodone self- administration. Finally, the contribution of IT and PT cells to morphine analgesia and opioid-induced tolerance and hyperalgesia will be assessed through chemogenetic suppression of mPFC IT or PT cells after acute and chronic morphine exposure in assays for thermal (hotplate) and mechanical (von Frey) pain. This project will establish foundational knowledge in the dissociation of the addictive and analgesic effects of opioids, illuminating targets for nonaddictive pain therapies. Through this research proposal and associated training plan, I will gain excellent training in neuroanatomy, addiction and pain behaviors, and neural dynamics in a supportive training environment at the University of North Carolina MD/PhD Program. This training will provide me with the technical and professional skills necessary to become a leader at an academic medical center and pursue my goals of practicing pain medicine and researching innovative non-addictive therapies for pain as a physician-scientist.

项目概要（摘要） mu 阿片受体 (MOR) 在整个神经系统中广泛表达，介导镇痛和镇痛作用。 和阿片类药物的成瘾作用。尽管美国目前存在阿片类药物危机，但阿片类药物仍提供 无与伦比的镇痛功效，适用于各种疼痛状况。解离阿片类镇痛药 和成瘾效应，有必要确定哪些神经回路和细胞类型介导这些效应 影响。由于 mPFC 功能，内侧前额叶皮层 (mPFC) 中的 MOR 信号传导具有特别重要的意义 作为上升和下降疼痛回路的关键整合节点及其与皮质下的强大连接 奖励电路。然而，阿片类药物最终如何改变谷氨酸能 mPFC 输出神经元的活性 调节阿片类药物成瘾和疼痛行为尚不清楚。皮层的主要输出包括两个不同的 第 5 层谷氨酸能投射神经元群体：端脑内 (IT) 和锥体束 (PT) 神经元。 IT 神经元主要投射到皮质内和纹状体，而 PT 神经元投射广泛并处于平衡状态 直接调节整个大脑的神经活动。尽管有证据支持 MOR 的作用 mPFC 在疼痛和成瘾中的作用，初步数据表明 MOR 并不直接在 IT 或 PT 细胞上表达。 该项目旨在 (1) 确定阿片类药物暴露如何影响小鼠 mPFC IT 和 PT 细胞活性，以及​​ (2) 描述 mPFC IT 和 PT 细胞对阿片类药物成瘾和镇痛的贡献。为了确定如何 阿片类药物调节 IT 和 PT 细胞活性，双色钙成像将用作神经元活动的代表。 每个群体的神经动力学将在基线、急性和慢性吗啡期间进行表征 通过皮下植入泵以及纳洛酮沉淀戒断期间暴露。评估 IT 和 PT 细胞对阿片类药物成瘾、mPFC IT 或 PT 细胞活性的贡献将通过化学遗传学来确定 在成瘾模型中受到抑制，包括吗啡条件位置偏爱和羟考酮自我 行政。最后，IT 和 PT 细胞对吗啡镇痛和阿片类药物诱导的耐受性的贡献 痛觉过敏将通过急性和慢性疼痛后 mPFC IT 或 PT 细胞的化学遗传学抑制来评估 热（热板）和机械（冯弗雷）疼痛测定中的慢性吗啡暴露。该项目将 建立阿片类药物成瘾和镇痛作用分离的基础知识， 阐明非成瘾性疼痛治疗的目标。 通过这个研究计划和相关的培训计划，我将获得神经解剖学方面的优秀培训， 北方大学支持性训练环境中的成瘾和疼痛行为以及神经动力学 卡罗莱纳州医学博士/博士项目。这次培训将为我提供必要的技术和专业技能 成为学术医疗中心的领导者并追求我实践疼痛医学的目标 作为一名医师科学家，研究创新的非成瘾性疼痛疗法。