Investigation of nociceptive endogenous opioid dynamics in the periaqueductal gray

导水管周围灰质伤害性内源性阿片类药物动力学研究

基本信息

批准号：
10579183
负责人：
Blake Kimmey
金额：
$ 7.45万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2022-02-03 至 2025-02-02
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579183
关键词：
Absence of pain sensation Acute Acute Pain Agonist Amygdaloid structure Analgesics Animals Attenuated Automobile Driving Brain Brain region Breathing Calcium Calcium Signaling Cells Central Medial Thalamic Nucleus Clinical Data Development Diffuse Disease Electric Stimulation Enkephalins Exhibits Fellowship Fiber Future Genetic Genetic Recombination Goals Health Human Hypersensitivity Interneurons Intervention Investigation Knowledge Label Leucine Enkephalin Ligands Light Mediating Molecular Morphine Mus Neural Pathways Neurons Neuropeptides Nociception Opioid Opioid Analgesics Opioid Peptide Opsin Overdose Pain Pain Measurement Pain management Pattern Peptides Persistent pain Persons Pharmaceutical Preparations Photometry Population Process Property Prosencephalon Quality of life Research Rewards Risk Role Signal Transduction Site Stimulus Structure System Testing Time Training Virus Work antinociception awake calcium indicator cell type chronic pain chronic pain management chronic pain patient chronic pain relief chronic painful condition endogenous opioids experience experimental study in vivo in vivo imaging inflammatory pain inward rectifier potassium channel midbrain central gray substance mu opioid receptors neural neural circuit novel opioid epidemic optogenetics overexpression pain perception pain relief pharmacologic postsynaptic pre-clinical prescription opioid presynaptic promoter recruit response sensor targeted treatment temporal measurement therapy outcome tool transmission process

项目摘要

PROJECT SUMMARY/ABSTRACT Chronic pain is a highly prevalent and debilitating clinical problem that negatively impacts the health and quality of life of millions of people. A common and relatively effective strategy to provide acute relief to chronic pain patients is through prescription of opioid compounds. However, opioid analgesics carry substantial abuse and overdose liabilities, contributing heavily to the ongoing opioid epidemic. These negative consequences of exogenous opioids result from their diffuse action at endogenous mu opioid receptor-expressing (MOR) brain regions beyond the pain-encoding neurocircuitry that they are intended to modulate. To meet the pressing demand for effective and safe analgesics, new, targeted pain therapies must be developed that emerge from focused research on the endogenous opioidergic cell types and neural circuits involved in pain perception (i.e., nociception) and opioid-induced analgesia. The ventrolateral periaqueductal gray (vlPAG) is critical in this regard as it can produce robust antinociception through MOR and the enkephalin peptides expressed by the cells and afferents it contains. Yet, long-standing questions remain concerning the endogenous opioid signaling dynamics in the vlPAG that are recruited by acute and chronic pain conditions. This proposal will begin to fill these gaps in knowledge with a combination of novel tools: genetic recombination in defined neural populations, MOR specific promoter viruses, and a fluorescent enkephalin sensor. Combined, these approaches allow for unprecedented in vivo access to the pre- and postsynaptic components of endogenous opioid transmission in the vlPAG. Thus, I will test my central hypothesis that the vlPAG contains a functional nociceptive MOR-expressing ensemble that is modulated by enkephalin release from forebrain and local interneurons to produce antinociception. In Aim 1, I will use classical pain assays to identify the molecular identity and calcium signaling activity patterns of the nociceptive MOR-expressing neural ensemble in the vlPAG (vlPAGNoci/MOR). I will further determine the functional role of vlPAGNoci/MOR neurons in antinociception through optogenetic inhibition during acute and inflammatory pain states. In Aim 2, I will identify and manipulate two putative enkephalinergic inputs to the vlPAG, local vlPAG interneurons and long-range medial nucleus of the central amygdala (CeM) projections, to determine their respective contributions to nociception. How these enkephalingeric afferents interact with the MOR-expressing neurons in the vlPAG will also be determined. The results of these proposed experiments will advance our understanding of endogenous opioid signaling processes that are engaged and altered by acute and chronic pain conditions. By elucidating the components of the endogenous opioid circuitry of the vlPAG that produce analgesia, relief from chronic pain may be realized by future therapies that target this system while lacking the harmful addictive properties of current opioid drugs. Completion of this Fellowship proposal will achieve my training goals to expand my experimental expertise and establish myself as an expert in pain and opioidergic neurocircuitry.

项目概要/摘要慢性疼痛是一种非常普遍且令人衰弱的临床问题，会对健康和健康产生负面影响。数百万人的生活质量。为慢性病患者提供急性缓解的常见且相对有效的策略患者的疼痛是通过阿片类化合物的处方来实现的。然而，阿片类镇痛药存在严重滥用和过量服用负债，严重助长了持续的阿片类药物流行。这些负面后果外源性阿片类药物是由于其在内源性 mu 阿片受体表达 (MOR) 大脑中的扩散作用而产生的它们要调节的疼痛编码神经回路之外的区域。为满足紧迫为了满足对有效和安全镇痛药的需求，必须开发新的、有针对性的疼痛疗法重点研究涉及疼痛感知的内源性阿片能细胞类型和神经回路（即，伤害感受）和阿片类药物引起的镇痛。腹外侧导水管周围灰质 (vlPAG) 在这方面至关重要因为它可以通过 MOR 和细胞表达的脑啡肽产生强大的镇痛作用它包含的传入。然而，关于内源性阿片类药物信号动力学的长期问题仍然存在急性和慢性疼痛情况下招募的 vlPAG 中。该提案将开始填补这些空白结合新工具的知识：定义的神经群体中的基因重组，MOR 特定的启动子病毒和荧光脑啡肽传感器。这些方法相结合，可以实现前所未有的体内获取 vlPAG 中内源性阿片类药物传输的突触前和突触后成分。因此，我将测试我的中心假设，即 vlPAG 包含一个功能性伤害感受 MOR 表达集合它受到前脑和局部中间神经元释放的脑啡肽的调节，以产生镇痛作用。瞄准 1，我将使用经典的疼痛测定来识别分子身份和钙信号传导活动模式 vlPAG 中表达伤害性 MOR 的神经系统 (vlPAGNoci/MOR)。我将进一步确定功能 vlPAGNoci/MOR 神经元在急性和炎症期间通过光遗传学抑制在抗伤害作用中的作用疼痛状态。在目标 2 中，我将识别并操纵 vlPAG 的两个假定的脑啡肽输入，即本地 vlPAG 中间神经元和中央杏仁核 (CeM) 投影的远程内侧核，以确定它们的分别对伤害感受的贡献。这些脑啡肽传入神经如何与 MOR 表达相互作用 vlPAG 中的神经元也将被确定。这些拟议实验的结果将推进我们的研究了解急性和慢性参与和改变的内源性阿片类信号传导过程疼痛情况。通过阐明产生阿片样物质的 vlPAG 内源性阿片样物质电路的组成部分镇痛，缓解慢性疼痛可能通过未来针对该系统的疗法来实现，但缺乏当前阿片类药物的有害成瘾特性。完成这项奖学金提案将实现我的目标培训目标是扩大我的实验专业知识，并使自己成为疼痛和阿片类药物方面的专家神经回路。