Lipid kinase regulation of nociceptive signaling and sensitization: Implications for analgesic drug development Public Deposited

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  • March 19, 2019
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  • Wright, Brittany Danielle
    • Affiliation: Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
Abstract
  • Chronic pain affects approximately 35% of American adults resulting in annual treatment costs over $600 billion. Unfortunately, current therapeutics have harmful side effects while only providing partial relief, highlighting the need for novel therapeutic targets for analgesic drug development. Neuropathic pain and inflammatory pain are the two most common forms of chronic pain in humans. In these conditions, nerve injury and inflammation lead to the release of pronociceptive molecules that signal through pronociceptive (pain-promoting) G protein-coupled receptors (GPCRs) and ion channels to sensitize nociceptive neurons in the dorsal root ganglia (DRG). Sensitization of these neurons leads to hyperalgesia and allodynia, two common symptoms of chronic pain. The majority of these pronociceptive receptors and ion channels signal via phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. However, it is currently unknown which lipid kinases generate PIP2 in DRG neurons and if these kinases regulate pronociceptive receptor signaling. The aim of this dissertation is to fully characterize the regulatory role of the predominant PIP2-synthesizing enzyme in nociceptive signaling and sensitization using a combination of genetic and pharmacological approaches. Our studies reveal that lipid kinase (LK) is expressed at the highest levels in DRG and, based on experiments with LK+/- mice, generates at least half of all PIP2 in DRG neurons. Moreover, LK haploinsufficiency reduced pronociceptive receptor signaling and ion channel-mediated neuronal excitability in DRG neurons and reduced noxious thermal and mechanical sensitization in mouse models of chronic pain via PIP2-dependent mechanism(s). In parallel, we developed a high-throughput screening assay to identify the first reported small molecule inhibitor of LK, UNC1. UNC1 lowered PIP2 levels in DRG neurons, reduced pronociceptive receptor signaling, and attenuated noxious thermal and mechanical sensitization when administered intrathecally. Collectively, this work demonstrates that LK regulates PIP2-dependent nociceptive signaling and sensitization and validates LK as a novel therapeutic target for chronic pain.
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  • In Copyright
Advisor
  • Zylka, Mark J.
Degree
  • Doctor of Philosophy
Graduation year
  • 2013
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