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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.

项目总结