An estimated 42,000 of the individuals living with spinal cord injury (SCI) are Veterans, which adds a significant health care burden to the Department of Veterans Affairs (VA) as SCI results in numerous long-term complications. One long-term complication is chronic pain, which is often rated among the most significant complaints of individuals with SCI. Opioids are prescribed to treat SCI-induced pain even though they have contributed to opioid misuse disorders and can actually worsen pain and delay recovery. Changes in nociceptor function, or the neurons that transmit pain, are thought to play a role in SCI-induced pain. Our lab has found that thoracic spinal contusion injury in mice results in the development of spontaneous pain behavior, nociceptor hypersensitivity, increased inflammation, and neuropathy in the skin. Our preliminary data also suggest that SCI causes mitochondrial dysfunction in the dorsal root ganglia (DRG), which is where neuronal cell bodies reside. Dysfunctional mitochondria are known to contribute to the secondary phase of SCI through production of reactive oxygen species (ROS), apoptosis, and aberrant calcium homeostasis, which can ultimately lead to neuronal cell death. Taken together, our data suggest that following SCI, neuronal mitochondria are not functioning properly, which could contribute to increased inflammation and neuropathy and subsequent development of nociceptor hypersensitivity and pain. Therefore, we are proposing the use of repeated heat treatment (rHT) following SCI in mice because this therapy has been shown to restore mitochondrial function, decrease mitochondrial ROS and inflammation, and improve pain outcomes. We will also determine if starting repeated rHT during either the acute or chronic phase of SCI, has different outcomes. Aim 1 of this proposal will determine the influence of rHT on SCI-induced pain, nociceptor dysfunction, and neuropathy while Aim 2 will determine the effect of rHT on mitochondrial function and content and ROS production following SCI. Aim 2 will also explore if targeting mitochondrial ROS with a mitochondrial specific antioxidant improves outcomes of SCI. We hypothesize that by restoring mitochondrial function and reducing widespread inflammation with rHT, nociceptor hypersensitivity, neuropathy, and pain will be attenuated. Dr. Eller’s background and training thus far make her a strong candidate for this award. She has mastered the SCI surgery and will now be trained by two experts, Dr. Kyle Baumbauer and Dr. John Thyfault, on techniques related to characterizing nociceptor and mitochondrial function, respectively. Her co-mentors are highly qualified scientists that have committed time and resources for Dr. Eller’s career development. In addition, the scientific environments at the University of Kansas Medical Center (KUMC) and the Kansas City VA Medical Center (VAMC) will allow Dr. Eller to not only complete the proposed research but also aid in her career development. She will expand her background knowledge in SCI and mitochondrial biology through relevant course work, seminars, and conferences. She will improve her presentation, writing, and mentoring skills by presenting her work at national conferences, publishing manuscripts, and teaching and mentoring graduate students. Finally, she will take the data generated from this proposal and apply for subsequent funding including a VA CDA-2 and NIH K01 award. Dr. Eller’s long-term goal is to establish herself as an independent VA Research Scientist and an expert in SCI pain. The CDA-1 would help her accomplish her goals by allowing her to learn new research techniques, expand her knowledge about SCI pain and mitochondria dysfunction, improve her writing and presentation skills, learn how to run a successful and ethical research program, and helping her integrate into the Kansas City VAMC. This award will also positively benefit the VA because the proposal addresses multiple areas of the VA RR&D service including a non-opioid and non-pharmacological therapy for chronic pain, a molecular study exploring the mechanisms of action of rehabilitative intervention by focusing on changes to the mitochondria, and the potential to translate to human subjects.

Many Veterans currently suffer from chronic pain associated with spinal cord injury (SCI). This persistent pain is resistant to current medical treatments, including opioids. Thus, there is a significant need for new, non-opioid therapeutic interventions for the treatment of SCI-associated pain. Two factors that we believe contribute to the development of chronic SCI pain include increased inflammation and metabolic dysfunction. Repeated whole body heat treatments are shown to decrease inflammation and restore metabolic health. Therefore, our proposed study uses repeated heat treatment after SCI in mice to determine if we can reduce inflammation, restore proper metabolic function, and subsequently attenuate SCI-associated chronic pain. We believe that this work could lead to broader clinical work in humans and ultimately enable the VA to offer a non- opioid and non-pharmacologic alternative to reduce SCI pain in Veterans.