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

7.项目总结/摘要 本提案旨在为助理阿曼达克莱因博士颁发K01指导研究科学家发展奖 美国加州大学药学实践和药物科学系教授 明尼苏达K01奖将为Klein博士提供必要的额外培训和经验， 成为一名独立的研究者，研究阿片类药物耐受性和戒断对外周 和中枢神经系统。卡罗琳费尔班克斯博士将担任主要导师与药物的专业知识 他还将监督培训计划。露西·弗查诺娃博士将提供 额外的指导，并在中枢神经系统成像方法方面有丰富的经验， 疼痛状况。拟议的职业发展计划包括重点突出的讲习班和研讨会， 导师从一组既定的研究人员，并实现新的研究技能。长期 这个K01职业奖的目标是有效地研究导致阿片耐受和戒断的机制 并为目前使用阿片类药物的慢性疼痛患者建立治疗靶点。阿片类药物治疗 已被证明在临床上有效地减少慢性疼痛;不幸的是，长期治疗 不良后果，包括镇静、耐受、滥用可能性和阿片类药物诱导的痛觉过敏（OIH） 当治疗停止时。 阿片类耐受性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， 阿片类药物耐受和阿片类药物治疗停止后的OIH，可以由外周血中的变化驱动。 神经系统（PNS）和中枢神经系统（CNS）。钾通道，如ATP敏感的 钾通道（KATP通道）在外周伤害感受器和二级神经元上表达， 有助于阿片类药物作为下游效应物的镇痛特性。建议的行为， 电生理学和成像方法对于理解KATP通道的作用是必不可少的 阿片类药物耐受前后的亚型。该K01奖的研究目标是：1）确定 PNS和CNS的KATP通道参与吗啡引起的神经病理性疼痛的维持 2）定量KATP通道亚型在耐受性中的位置、表达和功能的变化。 长期阿片类药物治疗前后外周（神经纤维）与中枢（脊髓）神经系统的比较 exposure.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性。未来的实验将进一步研究不同的 导致PNS和CNS中KATP通道表达和功能变化的细胞内途径。的 最终目标是使用KATP通道靶向药物来改善慢性疼痛状况， 缓解人类的耐受性和OIH，从而减少许多药物的不良副作用。 现有的阿片类药物治疗。

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.