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

7.项目摘要/摘要 这项建议是为助理阿曼达·克莱因博士颁发K01指导研究科学家发展奖 加州大学药学与实践系教授 明尼苏达州。K01奖将为克莱恩博士提供必要的额外培训和经验 成为研究外周阿片类药物耐受和戒断影响的独立研究员 和中枢神经系统。卡罗琳·费尔班克斯博士将担任具有药物专业知识的主要导师 给药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，并在慢性疾病的中枢神经系统成像方法方面拥有丰富的经验 疼痛状况。拟议的职业发展计划包括有重点的讲习班和研讨会， 来自一群知名研究人员的指导，并获得了新颖的研究技能。从长远来看 这个K01职业奖的目标是有效地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。阿片类药物治疗已经 在临床上被证明在减少慢性疼痛方面是有效的；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诱导的痛敏(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。 以前的文献表明， 阿片类药物耐受，以及阿片类药物治疗停止后的OIH，可以由外周细胞的变化驱动 神经系统(PNS)和中枢神经系统(CNS)。钾通道，如对三磷酸腺苷敏感 钾通道(KATP通道)在外周伤害性感受器和二级神经元上表达，以及 有助于阿片类药物作为下游效应物的止痛特性。建议的行为， 为了了解KATP通道的作用，电生理和成像方法是必不可少的 阿片耐受前后的亚型。该K01奖项的研究目标是：1)确定 三叉神经节和中枢神经系统的KATP通道参与吗啡持续的神经病理性疼痛 耐受性和2)量化KATP通道亚型的位置、表达和功能的变化 延长阿片类药物使用前后外周(神经纤维)与中枢(脊髓)神经系统的比较 曝光。初步数据表明，三叉神经节中特定KATP通道亚型的活性下降 而中枢神经系统有助于阿片类药物的耐受。未来的实验将进一步研究不同的 导致三叉神经节和中枢神经系统KATP通道表达和功能改变的细胞内通路。这个 最终目标是使用KATP通道靶向药物来改善慢性疼痛状况，同时 缓解人类的耐受性和OIH，从而减少许多 现有的阿片类药物疗法。

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.