Date of Award

Summer 8-23-2019

Level of Access

Open-Access Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Tamara King

Second Committee Member

Ian Meng

Third Committee Member

Derek Molliver

Additional Committee Members

Robert Burgess

Edward Bilsky

Abstract

Cancer-induced bone pain is reported to be one of the most detrimental aspects of the disease, often broadly categorized into two separate pain phenomena. Patients experience ongoing pain, a dull achy persistent background pain that worsens as disease progresses which is currently treated with around the clock mu opioid receptor (MOR) agonists such as morphine. Patients also report transient episodes of severe pain that is spontaneous but often triggered by movement that “breaks through” around the clock medication. Breakthrough pain is treated with additional rapid onset MOR agonists that are hindered by dose-limiting side effects and often misalign with treatment for patients. The failure of current medications to effectively treat patients and undesirable side effects of MOR agonists highlights the need to develop novel treatments. We examined the hypothesis that ongoing pain and breakthrough pain are mitigated by unique populations of sensory afferents. Utilizing a rat model of cancer-induced bone pain (CIBP) that implants MATBIII adenocarcinoma cells into the tibia of Fischer rats, we demonstrate that IB4-binding fibers play a critical role in transducing breakthrough pain, whereas TRPV1 expressing fibers do not. Limitations of the chemo-ablative approach used to target these neurons directed work to a mouse model of CIBP that relies on implantation of Lewis lung carcinoma cells into the femur of C57BL/6 mice. Utilizing Nav1.8-Cre and MrgD-Cre-ERT2 mouse lines, targeted expression of the light sensitive proton pump ArchT allowed for the inhibition of neurons in animals with CIBP. Using conditioned place preference to pain relief, we demonstrate that inhibition of Nav1.8 fibers relieves ongoing pain, and silencing MrgD fibers in tumor-bearing animals results in conditioned place preference. We also describe a potential approach to measure breakthrough pain in the mouse, but did not characterize it. This work provides evidence to target these populations of sensory neurons to develop treatments in an effort to reduce and treat cancerinduced ongoing and breakthrough pain. The implication of non-peptidergic neurons to convey components of cancer-induced bone pain is a novel finding and distinguishes them for a unique role in CIBP from other work in the pain field.

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