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.
Opioids are commonly used to treat chronic pain, however after prolonged use their clinical effectiveness is reduced due to undesirable side effects such as tolerance and opiate induced hyperalgesia after treatment has stopped. Activation of downstream mediators, such as specific potassium channels located on peripheral nerve terminals, could reduce the doses of opioids needed to achieve analgesia, alleviate tolerance due to opiate receptor inactivation and lessen symptoms of withdrawal. The proposed studies will investigate the involvement of ATP sensitive potassium channels, during chronic opiate treatment and provide information needed in order to apply this therapy for medical applications.