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.

项目摘要/摘要慢性疼痛是一个高度普遍且令人衰弱的临床问题，对健康和数百万人的生活质量。一种常见且相对有效的策略，可为慢性提供急性缓解疼痛患者是通过处方阿片化合物的处方。但是，阿片类镇痛药遭受大量虐待和过量的责任，对正在进行的阿片类药物流行产生了重大贡献。这些负面后果外源阿片类药物是由于其在表达阿片类药物受体（MOR）脑的弥漫性作用而产生的它们旨在调节的疼痛编码神经记录的区域。遇到紧迫的必须开发出对有效和安全的镇痛药，新的，有针对性的疼痛疗法的需求针对疼痛感知的内源性阿片类细胞类型和神经回路的重点研究（即伤害感受）和阿片类药物诱导的镇痛。在这方面因为它可以通过细胞表达的MOR和Enkephalin肽以及它包含的传入。然而，关于内源性阿片类药物信号传导动力学的长期问题仍然存在在通过急性和慢性疼痛条件招募的VLPAG中。该建议将开始填补这些空白与新工具相结合的知识：定义的神经种群中的遗传重组，特定于MOR 启动子病毒和荧光enkephalin传感器。这些方法结合在一起，允许前所未有体内访问VLPAG中内源性阿片类药物传播的突触前和后成分。因此，我将测试我的中心假设，即VLPAG包含功能性伤害性表达合奏这是由邻脑和局部神经元释放以产生抗伤害感受的调节。目标 1，我将使用经典的疼痛测定来确定分子身份和钙信号传导活性模式 VLPAG（VLPAGNOCI/MOR）中的伤害性表达神经合奏。我将进一步确定功能 VLPAGNOCI/MOR神经元在急性和炎症过程中通过光遗传学抑制作用在抗伤害感受中的作用疼痛状态。在AIM 2中，我将识别并操纵两个推定的enkephalinergic输入到VLPAG，本地VLPAG 中央杏仁核（CEM）投影的中间神经元和远程内侧核，以确定其各自对伤害感受的贡献。这些Enkephalingeric传入如何与表达的表达相互作用 VLPAG中的神经元也将得到确定。这些提出的实验的结果将推动我们的了解因急性和慢性而参与和改变的内源性阿片类药物信号传导过程疼痛条件。通过阐明产生的VLPAG的内源性阿片类电路的成分镇痛，可以通过针对该系统的未来疗法来实现慢性疼痛的缓解当前阿片类药物的有害成瘾性。该奖学金提案的完成将实现我的培训目标以扩大我的实验专业知识，并确立自己的痛苦和阿片类动物专家神经记录。