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） μ阿片受体（莫尔）在整个神经系统中广泛表达，并介导镇痛和抗氧化。 以及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，但阿片类药物提供了 无与伦比的镇痛效果，并规定用于各种疼痛条件。分离阿片类镇痛药 和上瘾的影响，这是至关重要的，以确定哪些神经回路和细胞类型介导的每一个这些 方面的影响.内侧前额叶皮层（mPFC）的莫尔信号传导由于mPFC功能而具有特别重要的意义 作为上行和下行疼痛回路的关键整合节点， 奖励电路然而，阿片类药物如何最终改变多巴胺能mPFC输出神经元的活性， 调节阿片类药物成瘾和疼痛行为是未知的。大脑皮层的主要输出包括两种不同的 第5层丘脑投射神经元群：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神经元广泛投射， 直接调节整个大脑的神经活动。尽管有证据支持MOR依赖的作用， mPFC在疼痛和成瘾中的作用，初步数据表明，莫尔不直接在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的mPFC IT和PT细胞活性，以及（2） 描述mPFC IT和PT细胞对阿片成瘾和镇痛的贡献。以确定如何 阿片类调节IT和PT细胞活性，双色钙成像将用作神经元活性的代表。 每个群体的神经动力学将在基线、急性和慢性吗啡给药期间进行表征。 通过皮下植入泵暴露，以及在纳洛酮催促戒断期间。评估 IT和PT细胞对阿片类药物成瘾的贡献，mPFC IT或PT细胞活性将在化学发生学上 抑制成瘾模型，包括吗啡条件性位置偏爱和羟考酮自我- 局最后，研究了IT和PT细胞在吗啡镇痛和阿片耐受中的作用。 和痛觉过敏将通过在急性和慢性刺激后对mPFC IT或PT细胞的化学发生抑制来评估， 在热（热板）和机械（von Frey）疼痛试验中的慢性吗啡暴露。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， 为非成瘾性疼痛治疗提供了新的思路 通过这项研究计划和相关的培训计划，我将获得良好的神经解剖学培训， 成瘾和疼痛行为，以及神经动力学的支持性训练环境在北方大学 卡罗莱纳医学博士/博士项目。该培训将为我提供必要的技术和专业技能， 成为一个学术医疗中心的领导者，追求我的疼痛医学实践目标， 作为一名医生兼科学家，研究创新的非成瘾性疼痛疗法。