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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：
10388958
负责人：
Blake Kimmey
金额：
$ 7.03万
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/10388958
关键词：
Absence of pain sensation Acute Acute Pain Acute inflammatory 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 Foundations Future Genetic Genetic Recombination Goals Health Hypersensitivity Interneurons Intervention Investigation Knowledge Label Leucine Enkephalin Ligands Light Mediating Methionine Enkephalin Molecular Morphine Mus Neural Pathways Neurons Neuropeptides Nociception Opioid Opioid Analgesics Opioid Peptide Opsin Overdose Pain Pain Measurement Pain management Pattern Peptides Perception Persistent pain Persons Pharmaceutical Preparations Pharmacology Photometry Population Process Property Prosencephalon Quality of life Research Rewards Risk Role Signal Transduction Site Stimulus Structure System Testing Time Training Virus Work 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 circuit novel opioid epidemic optogenetics overexpression pain perception pain relief postsynaptic pre-clinical prescription opioid promoter recruit relating to nervous system 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.

项目总结/文摘