Altering potassium channel activity to investigate morphine tolerance and opiate induced hypersensitivity

改变钾通道活性以研究吗啡耐受性和阿片类药物引起的超敏反应

基本信息

批准号：
10349435
负责人：
Amanda Helen Klein
金额：
$ 14.2万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10349435
关键词：
ATP sensitive potassium channel complex Absence of pain sensation Action Potentials Adenylate Cyclase Afferent Neurons Aftercare Analgesics Animals Attenuated Award Behavioral CRSP3 gene Calcium Chronic Clinic Clinical effectiveness Data Development Development Plans Dose Drug Delivery Systems Educational workshop Electrophysiology (science)Future Goals Histologic Human Hyperalgesia Hypersensitivity Individual International Lead Ligation Literature Location Maintenance Mechanics Mediator of activation protein Medical Mentored Research Scientist Development Award Mentors Mentorship Methods Minnesota Morphine Mus Nerve Nerve Fibers Nervous system structure Neuraxis Neurons Neuropathy Nociceptors Opioid Opioid Analgesics Opioid Receptor Pain Threshold Pathway interactions Peripheral Peripheral Nerves Peripheral Nervous System Pharmaceutical Preparations Pharmacologic Substance Pharmacy (field)Pharmacy facility Phosphotransferases Potassium Channel Preparation Property Receptor Activation Research Research Personnel Rodent Role Science Sedation procedure Signal Pathway Skin Slice Spinal Cord Spinal nerve structure System Training Universities Withdrawal Symptom abuse liability addiction associated symptom base career career development chronic pain chronic pain management chronic pain patient chronic pain relief chronic painful condition desensitization experience experimental study imaging modality imaging study improved morphine tolerance mu opioid receptors nervous system imaging novel opiate tolerance opioid exposure opioid therapy opioid use opioid withdrawal pain model pain symptom painful neuropathy prescription opioid professor receptive field receptor reduce symptoms side effect skills theories therapeutic target

项目摘要

7. Project Summary/Abstract This proposal is for a K01 Mentored Research Scientist Development Award for Dr. Amanda Klein, Assistant Professor in the Department of Pharmacy Practice and Pharmaceutical Sciences at the University of Minnesota. The K01 award will provide Dr. Klein with the additional training and experience necessary to become an independent investigator studying the effects of opioid tolerance and withdrawal in the peripheral and central nervous system. Dr. Carolyn Fairbanks will serve as the primary mentor with expertise in drug delivery methods and opioid tolerance, and will oversee the training plan. Dr. Lucy Vulchanova will provide additional mentorship and has extensive experience in central nervous system imaging methods during chronic pain conditions. The proposed career development plan includes focused workshops and seminars, mentorship from a group of established researchers, and the attainment novel research skills. The long term goal of this K01 career award is effectively study the mechanisms that lead to opioid tolerance and withdrawal and to establish therapeutic targets for chronic pain patients current on opioid medications. Opioid therapy has been shown to be effective in reducing chronic pain in the clinic; unfortunately, long term treatment has negative consequences, including sedation, tolerance, abuse potential and opioid induced hyperalgesia (OIH) when treatment is stopped. Opioid tolerance is potentially due to receptor desensitization and/or a functional uncoupling of opioid receptors from their effector systems. Previous literature suggests that mechanisms of opioid tolerance, and OIH after opioid treatment has ceased, can be driven by changes in the peripheral nervous system (PNS) and central nervous system (CNS). Potassium channels, such as ATP sensitive potassium channels (KATP channels) are expressed on peripheral nociceptors and second order neurons, and contribute to the analgesic properties of opioids as downstream effectors. The proposed behavioral, electrophysiological, and imaging methods are essential in order to understand the role of KATP channels subtypes before and after opioid tolerance. The research objectives of this K01 award are to: 1) Identify the involvement of KATP channels in the PNS and CNS in the maintenance of neuropathic pain during morphine tolerance and 2) Quantify the changes in location, expression and function of KATP channel subtypes in peripheral (nerve fibers) versus central (spinal cord) nervous system before and after prolonged opioid exposure. Preliminary data suggest that a decrease in activity of specific KATP channel subtypes in the PNS versus the CNS contribute to opioid tolerance. Future experiments will further investigate the diverse intracellular pathways leading to changes in KATP channel expression and function in the PNS and CNS. The ultimate goal is to use KATP channel targeting pharmaceutics to improve chronic pain conditions while alleviating tolerance and OIH in humans and therefore decrease the adverse side effects seen with many existing opioid therapies.

7. 项目总结/摘要本提案旨在为助理 Amanda Klein 博士颁发 K01 指导研究科学家发展奖英国大学药学实践与药学系教授明尼苏达州。 K01 奖项将为克莱因博士提供必要的额外培训和经验成为一名独立研究者，研究阿片类药物耐受和戒断对外周血管的影响和中枢神经系统。 Carolyn Fairbanks 博士将担任具有药物专业知识的主要导师交付方法和阿片类药物耐受性，并将监督培训计划。 Lucy Vulchanova 博士将提供额外的指导，并在慢性病期间的中枢神经系统成像方法方面拥有丰富的经验疼痛情况。拟议的职业发展计划包括重点讲习班和研讨会，来自一群知名研究人员的指导，以及取得新颖的研究技能。长期来看 K01 职业奖的目标是有效研究导致阿片类药物耐受和戒断的机制并为目前使用阿片类药物的慢性疼痛患者建立治疗目标。阿片类药物治疗有临床显示可有效减轻慢性疼痛；不幸的是，长期治疗已经负面后果，包括镇静、耐受、滥用潜力和阿片类药物引起的痛觉过敏 (OIH) 当治疗停止时。阿片类药物耐受可能是由于受体脱敏和/或功能性阿片受体与其效应系统的解偶联。先前的文献表明，阿片类药物耐受性以及阿片类药物治疗停止后的 OIH 可能是由外周血管变化引起的神经系统（PNS）和中枢神经系统（CNS）。钾通道，例如 ATP 敏感通道钾通道（KATP 通道）在外周伤害感受器和二级神经元上表达，并且作为下游效应器，有助于阿片类药物的镇痛特性。拟议的行为，电生理学和成像方法对于了解 KATP 通道的作用至关重要阿片类药物耐受之前和之后的亚型。该 K01 奖项的研究目标是： 1) 确定 PNS 和 CNS 中的 KATP 通道参与维持吗啡期间的神经性疼痛耐受性和 2) 量化 KATP 通道亚型的位置、表达和功能的变化长期使用阿片类药物之前和之后的外周（神经纤维）与中枢（脊髓）神经系统接触。初步数据表明，PNS 中特定 KATP 通道亚型的活性降低与中枢神经系统相比，有助于阿片类药物耐受。未来的实验将进一步研究不同的细胞内途径导致 PNS 和 CNS 中 KATP 通道表达和功能的变化。这最终目标是利用 KATP 通道靶向药物来改善慢性疼痛状况，同时减轻人类的耐受性和 OIH，从而减少许多不良副作用现有的阿片类药物疗法。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reduced activity of adenylyl cyclase 1 attenuates morphine induced hyperalgesia and inflammatory pain in mice.

降低腺苷酸环化酶 1 的活性可减轻吗啡引起的小鼠痛觉过敏和炎性疼痛。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Johnson, Kayla;Doucette, Alexis;Edwards, Alexis;Verdi, Aleeya;McFarland, Ryan;Hulke, Shelby;Fowler, Amanda;Watts, Val J;Klein, Amanda H
通讯作者：
Klein, Amanda H

Modulation of SUR1 KATP Channel Subunit Activity in the Peripheral Nervous System Reduces Mechanical Hyperalgesia after Nerve Injury in Mice.

调节周围神经系统中的 SUR1 KATP 通道亚基活性可减少小鼠神经损伤后的机械性痛觉过敏。

DOI：
发表时间：
2019-05-07
期刊：
影响因子：
5.6
作者：
Luu, Wing;Bjork, James;Salo, Erin;Entenmann, Nicole;Jurgenson, Taylor;Fisher, Cole;Klein, Amanda H
通讯作者：
Klein, Amanda H

KATP Channel Prodrugs Reduce Inflammatory and Neuropathic Hypersensitivity, Morphine-Induced Hypersensitivity, and Precipitated Withdrawal in Mice.

KATP 通道前药可减轻小鼠的炎症和神经性超敏反应、吗啡引起的超敏反应和突然戒断反应。

DOI：
发表时间：
2023-10
期刊：
影响因子：
0
作者：
Doucette, Alexis;Johnson, Kayla;Hulke, Shelby;Mujteba, Sunna;Miller, Elena;Meyer, Belle;Dosa, Peter I;Klein, Amanda H
通讯作者：
Klein, Amanda H

Morphine Efficacy, Tolerance, and Hypersensitivity Are Altered After Modulation of SUR1 Subtype KATP Channel Activity in Mice.

调节小鼠 SUR1 亚型 KATP 通道活性后，吗啡的功效、耐受性和超敏性发生改变。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Fisher, Cole;Johnson, Kayla;Okerman, Travis;Jurgenson, Taylor;Nickell, Austin;Salo, Erin;Moore, Madelyn;Doucette, Alexis;Bjork, James;Klein, Amanda H
通讯作者：
Klein, Amanda H

The orotrigeminal system.

口三叉神经系统。