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http://hdl.handle.net/11375/25383
Title: | STUDIES ON THE PATHOPHYSIOLOGY OF CANCER-INDUCED BONE PAIN |
Authors: | Ungard, Robert G |
Advisor: | Singh, Gurmit |
Department: | Health Sciences |
Keywords: | Pain;Cancer;Cancer Pain;Cancer-Induced Bone Pain;System xC-;xCT;SLC7A11;Progesterone;Pregabalin;Electrophysiology;RNA-Seq;Neuroprotection |
Publication Date: | 2020 |
Abstract: | Metastatic bone cancers cause severe symptoms including pain that compromises patient functional status, quality of life, and survival. Current treatment strategies have limited efficacy and dose-limiting side effects. Cancer-induced bone pain (CIBP) is a unique pain state that shares features with but is distinct from the pathology of neuropathic and inflammatory pain. This dissertation investigates how CIBP is generated and maintained by the direct effects of cancer cells on their metastatic microenvironment and the peripheral nervous system, including unique signaling properties and gene expression changes. In particular, we found that genetic knockdown of the functional subunit xCT of the system xC- cystine/glutamate antiporter can reduce CIBP, further elucidating this as a therapeutic of interest. We found that the neuroprotective voltage-gated calcium channel inhibitors progesterone and pregabalin markedly reduce mechanical hypersensitivity and excitability in sensory neurons of the dorsal root ganglion (DRG) in male rat models of neuropathic pain, but that these effects and less pronounced in females. In cancer pain, these sex differences are reversed, with females but not males demonstrating a delay in time-to-onset of mechanical hypersensitivity. We also analyzed gene expression at the DRG by RNA-Sequencing of rat models of CIBP. Our findings uncovered differential gene expression between CIBP and sham controls and between ipsilateral and contralateral DRGs in CIBP model rats. These studies have identified several promising avenues for therapeutic research for CIBP. |
URI: | http://hdl.handle.net/11375/25383 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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ungard_robert_g_202004_phd.pdf | 4.27 MB | Adobe PDF | View/Open |
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