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KATP Channels as Downstream targets of adenylyl cyclases during opioid tolerance and withdrawal

KATP 通道作为阿片类药物耐受和戒断期间腺苷酸环化酶的下游靶标

基本信息

批准号：
10451672
负责人：
Amanda Helen Klein
金额：
$ 56.27万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10451672
关键词：
ATP sensitive potassium channel complex Acute Address Adenoviruses Adenylate Cyclase Affect Agonist Analgesics Attenuated Basic Science Cells Chronic Chronic inflammatory pain Clinical Coupled Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Down-Regulation Drug Targeting Drug usage Electrophysiology (science)Exposure to Financial cost Future G-Protein-Coupled Receptors GTP-Binding Proteins Goals Human Hypersensitivity Hypertrophy In Situ Hybridization In Vitro Incidence Intervention Intrathecal Injections Knowledge Lead Mechanics Mediator of activation protein Mission Molecular Morphine Mus National Institute of Drug Abuse Nerve Fibers Nervous system structure Neural Conduction Neuraxis Neurons Nociceptors Opioid Opioid agonist Outcome Patients Peripheral Pharmacology Play Potassium Potassium Channel Protein Isoforms Public Health Recording of previous events Research Rodent Model Signal Transduction Signal Transduction Pathway Spinal Cord Spinal Ganglia Therapeutic United States Up-Regulation Viral Vector Withdrawal Withdrawal Symptom Work adenylyl cyclase 1 antagonist base chronic pain relief combat drug development genetic approach genetic predictors improved in vitro Assay in vitro activity in vivo innovation knock-down mu opioid receptors neurobiological mechanism neuronal excitability neurophysiology novel novel therapeutics opiate tolerance opioid abuse opioid exposure opioid misuse opioid use opioid withdrawal pain patient pain processing pain signal prescription opioid prevent response sciatic nerve spontaneous pain

项目摘要

Project Summary The proposed research is relevant to public health because opioid use is prevalent in the United States and the human and financial costs associated with tolerance and withdrawal are at crisis levels. In order to reduce opioid abuse and misuse, our long-term goal is to determine the intracellular mechanisms to lead to these clinical problems. The objective of the proposed research is to understand the molecular involvement of adenylyl cyclase signaling and potassium channels in the peripheral and central nervous system during chronic opioid exposure using rodent models. A great deal of work has been done investigating the paradoxical phenomena of hypertrophied adenylyl cyclase activity and expression that occurs during chronic opioid exposure. The central hypothesis is that increased activity adenylyl cyclase and downstream mediators decrease KATP channel activity, leading to neuronal depolarization and increased hypersensitivity and spontaneous pain. The rationale of this proposal is that its completion will identify key intracellular targets of adenylyl cyclases, including potassium channels such as ATP-sensitive potassium (KATP) channels, which will help us to classify molecules that alter neuronal excitability and may play a key role in hypersensitivity during chronic opioid exposure. Given the history of research into adenylyl cyclase and inhibitory G-protein coupled signaling in the nervous system, it is surprising that fundamental questions still exist as to how these molecules affect neurophysiology of pain processing. Our first hypothesis is that overall expression of adenylyl cyclase 1 in the dorsal root ganglia and spinal cord increases after chronic morphine exposure. Our second hypothesis is that upregulation of adenylyl cyclase 1, and consequently cAMP, protein kinase A, and Epac molecules decrease KATP channel activity in vitro. Our third hypothesis is that upregulation of KATP channel subunits in the dorsal root ganglia and spinal cord using intrathecal injection of adenovirus viral vectors will improve mechanical hypersensitivity, mobility, and nerve conduction in mice after upregulated adenylyl cyclase during chronic opioid exposure. These approaches should prove to be complementary to one another and will provide the greatest opportunity to observe changes that occur in the nervous system after chronic opioid exposure. We plan on addressing these hypotheses through an innovative combination of in situ hybridization, electrophysiology, and potassium flux assays in vitro, and genetic approaches in vivo. The proposed work is important because completion of these studies will determine if the inverse relationship between adenylyl cyclase and KATP channel functionality could ultimately underlie and promote pain signaling seen clinically during opioid tolerance and withdrawal. KATP channels present an unutilized and interesting target for the development of drugs to treat opioid abuse and misuse. These results will have a positive impact because they will provide an increased knowledge and understanding of these signal transduction pathways during opioid exposure may assist in the mission to find better alternatives to current analgesic therapies for patients.

项目摘要这项拟议的研究与公共健康有关，因为阿片类药物的使用在美国很普遍，人类和与容忍和退出相关的财务成本处于危机水平。为了减少阿片类药物滥用和误用，我们的长期目标是确定导致这些临床问题的细胞内机制。该计划的目标是拟开展的研究旨在了解腺苷环化酶信号转导和钾通道在心肌梗死中的分子参与。使用啮齿动物模型研究慢性阿片类药物暴露期间的外周和中枢神经系统。已经做了大量的工作对腺苷环化酶活性和表达的矛盾现象进行了研究在慢性阿片类药物暴露期间。中心假说是腺酰环化酶的活性增加和下游介质降低KATP通道活性，导致神经元去极化和超敏反应增加。自发性疼痛。这项提议的基本原理是，它的完成将确定腺苷酸的关键细胞内靶标循环酶，包括钾通道，如三磷酸腺苷敏感钾(KATP)通道，这将有助于我们分类改变神经元兴奋性的分子，可能在慢性阿片类药物暴露期间的超敏反应中发挥关键作用。考虑到神经系统中腺苷酸环化酶和抑制性G蛋白偶联信号的研究历史，它是令人惊讶的是，关于这些分子如何影响疼痛处理的神经生理学，基本问题仍然存在。我们的第一个假说是腺苷环化酶1在背根节和脊髓中的总体表达增加长期接触吗啡。我们的第二个假设是腺酰环化酶1的上调，因此cAMP，蛋白激酶A和EPAC分子在体外降低KATP通道活性。我们的第三个假设是鞘内注入腺病毒载体后，背根神经节和脊髓中KATP通道亚单位将上调腺酰环化酶可改善小鼠的机械超敏反应、活动能力和神经传导慢性阿片类药物暴露。这些方法应该被证明是相辅相成的，并将提供最大的有机会观察慢性阿片类药物暴露后神经系统发生的变化。我们计划解决这些假说是通过创新地结合原位杂交、电生理学和钾通量分析得出的。在体外，以及在体内的遗传方法。拟议的工作很重要，因为完成这些研究将确定腺酰环化酶和KATP通道功能之间的反向关系是否最终可能是基础并促进临床上在阿片类药物耐受和戒断期间出现的疼痛信号。KATP通道呈现未利用状态以及治疗阿片类药物滥用和误用的药物开发的有趣目标。这些结果将产生积极的影响影响，因为它们将增加对这些信号转导途径的了解和理解阿片类药物的暴露可能有助于为患者寻找目前止痛疗法的更好替代方案。