Date of Award

Summer 8-19-2022

Level of Access Assigned by Author

Open-Access Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Geoffrey Ganter

Second Committee Member

Ian Meng

Third Committee Member

Kristy Townsend

Additional Committee Members

Robert Burgess

Vicki Losick

Abstract

Abnormal pain affects ~50 million adults nationwide. With many of the current treatment options for chronic pain, such as opioid analgesics, carrying side effects such as the threat for addiction, research into safer and more effective options for chronic pain relief is crucial. Abnormal alterations in nociceptive sensitivity, which is the sensitivity of peripheral sensory neurons that detect noxious stimuli, can underlie, and perpetuate chronic pain. However, much is still unknown about the mechanism of how these abnormal alterations in sensitivity occur. To help elucidate genetic components controlling nociceptive sensitivity, the Drosophila melanogaster larval nociception model has been used to characterize well-conserved pathways through the use of genetic modification and/or ultraviolet (UV) irradiation injury to alter the sensitivity of experimental animals. We have continued to build upon this knowledge to reveal a more complete system for how nociceptive sensitivity can be altered, even without injury, by investigation into the potential roles of other novel genes/signaling pathways including, Arm, a component within the Wnt/Wg signaling pathway. Our findings indicate Arm to be a facilitator in controlling nociceptive sensitivity in the absence of injury, by maintaining baseline sensitivity. In an effort to also explore the mechanisms of the primary nociceptors (nociceptors which directly detect noxious stimuli), we conducted bioinformatic analysis of RNA transcripts derived specifically from the nociceptors of larvae after UV injury. Results from this effort led to the discovery of a downregulation in serine proteases during peak allodynia (when something not normally noxious becomes so) development. Results also led to the hypothesis that upregulated Rgk1 and AnxB11 were involved in recovery of the nociceptor from hyperalgesia. This was supported by the knockdown of Rgk1 and AnxB11 having led to nociceptor hypersensitivity in larvae. And in an effort to move the methodology of our field forward, and because the larval stages of fruit fly development are relatively brief, we developed a methodology that allows longer term experimentation of nociceptive sensitization after injury in adult fruit flies. Ultimately, our research uncovered components involved in nociceptive sensitivity, which will hopefully lead to uncovering better treatment options for abnormal pain in the future.

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