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ATB_Thesis_FINAL_26July22.pdf

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CELLULAR AND BEHAVIORAL CHARACTARIZATION OF δ-OPIOID RECEPTOR MEDIATED ß-ARRESTIN SIGNALING

thesis
posted on 2022-07-26, 20:14 authored by Arryn T BlaineArryn T Blaine

The following thesis will focus on understanding the downstream behavioral effects of δORmediated β-arrestinsignaling. δORagonists have been implicated as effective targets for a variety of diseases, however detrimental side effects of opioid-targeting agonists limit their clinical use. δORagonists specifically can induce seizures, however the underlying mechanism contributing to this  behavior  is  unknown.  We  review  this  phenomenon  in  more  detail,  highlighting  current agonists known to induce seizures and potential circuits and pathways involved. Our work suggests β-arrestinsignaling  is  involved,  specifically β-arrestin2  mediated  signaling  may  be  largely contributing  to δORagonist-induced  seizure  behavior.  As  it  is  possible  the β-arrestinisoforms have unique roles in seizure behavior, we also analyzed methods in which to provoke β-arrestinisoform bias of δORtargeting compounds. Though the full mechanism relating δORagonists with seizures remains unknown, our work provides foundational detail of this behavior, implicating the importance of β-arrestinisoform signaling through δOR; allowing for future studies to full define this seizure pathway and develop δORsafer agonists.  

History

Degree Type

  • Doctor of Philosophy

Department

  • Medicinal Chemistry and Molecular Pharmacology

Campus location

  • West Lafayette

Advisor/Supervisor/Committee Chair

Richard van Rijn

Additional Committee Member 2

Angeline Lyon

Additional Committee Member 3

Julia Chester

Additional Committee Member 4

Val Watts