ResearchWorks Archive
    • Login
    View Item 
    •   ResearchWorks Home
    • Dissertations and Theses
    • Pharmacology
    • View Item
    •   ResearchWorks Home
    • Dissertations and Theses
    • Pharmacology
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Mechanisms of Opioid Receptor Desensitization

    Thumbnail
    View/Open
    Kuhar_washington_0250E_15024.pdf (2.312Mb)
    Author
    Kuhar, Jamie Rose
    Metadata
    Show full item record
    Abstract
    Agonists targeting MOR are effective analgesics, but their clinical use is hindered by side effects, including tolerance and addiction. KOR agonists also produce analgesia, but clinical use of these compounds has remained minimal due to aversive properties in humans. The µ-opioid receptor (MOR) agonists, morphine and fentanyl, both activate c-Jun N-terminal kinase (JNK), which is required for spinally-mediated morphine acute analgesic tolerance, whereas acute analgesic tolerance to fentanyl is blocked by G protein-coupled receptor kinase 3 (GRK3) gene deletion. Similarly, the κ-opioid receptor (KOR) collateral antagonist, norBNI, stimulates phosphorylation of JNK, and JNK1 is specifically required for norBNI’s long duration of antagonism. The durations of action of a broad range of KOR antagonists, including norBNI, positively correlate with the ability of the antagonist to activate JNK1 (Melief et al., 2011), whereas there is no correlation between duration of antagonist action and drug clearance (Munro et al., 2012). A better understanding of the mechanisms that contribute to opioid receptor desensitization is necessary for the development of improved therapeutics that avoid tolerance. This JNK-mediated mechanism of desensitization is likely to be more broadly applicable across the myriad of other GPCR systems. Additionally, elucidating the circuits responsible for p38-dependent, KOR-mediated aversion will assist with the development of KOR analgesics that avoid classic MOR side effects. Therefore, the goal of my thesis project has been to identify ligand-directed signaling mechanisms that contribute to JNK activation following morphine and fentanyl administration and better understand how JNK activation promotes MOR and KOR desensitization. Additionally, this thesis describes efforts to identify G biased KOR compounds with a reduced potential to cause dysphoria. Ultimately, this work provides a deeper understanding of opioid receptor signaling and can provide the basis for future therapeutic development targeting this receptor system.
    URI
    http://hdl.handle.net/1773/34122
    Collections
    • Pharmacology [71]

    DSpace software copyright © 2002-2015  DuraSpace
    Contact Us | Send Feedback
    Theme by 
    @mire NV
     

     

    Browse

    All of ResearchWorksCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects

    My Account

    LoginRegister

    DSpace software copyright © 2002-2015  DuraSpace
    Contact Us | Send Feedback
    Theme by 
    @mire NV