Project Details
Description
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.
Status | Finished |
---|---|
Effective start/end date | 3/1/18 → 2/28/23 |
Funding
- National Institute on Drug Abuse: $144,152.00
- National Institute on Drug Abuse: $145,826.00
- National Institute on Drug Abuse: $141,988.00
- National Institute on Drug Abuse: $147,068.00
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