Project Summary/Abstract Chronic pain is the most common cause of long-term disability with an estimated 20.4% of U.S. adults had chronic pain in 2016 and an estimated $560 billion each year in direct medical costs, lost productivity, and disability programs. Despite this immense impact, there are insufficient therapeutic options for pain and those that do improve patient conditions become less impactful over time. In addition, stress-induced psychological disorders such as anxiety, depression, and pain catastrophizing have been associated with poor prognosis in people with pain conditions. There is a need to develop alternative approaches to pain research to tackle this systemic problem. Focusing efforts on broader neuronal systems that influence the mechanistic processes associated with pain may be a viable novel approach. More specifically, investigating mechanisms by which homeostatic pain processing is altered by stress will aid in isolating neurobiological underpinnings of chronic pain. Here, we focus on the locus coeruleus norepinephrine system as a nexus of stress and pain processing. In this proposal we will characterize the role of the LC-NE system in modulating stress-induced changes to nociception at cellular, circuit, and network levels. We hypothesize the LC-NE system is a critical component to the process by which stress influences nociceptive output. We will test this hypothesis in a series of experimental aims. Aim 1 will test the hypothesis that LC-NE activity is required exclusively during the processing of an external stressor to ultimately result in an antinociceptive effect. Aim 2 will investigate the hypothesis that LC-NE terminal activity in the dorsal raphe nucleus (DRN) is a required step within the broader mechanism of stress-induced antinociception. Specifically, we have proposed experiments to determine whether LC-DRN circuit activation is potentiated in response to noxious stimuli after stress exposure and whether 1-adrenergic receptors within the DRN are required for stress-induced antinociception. The results will provide a better understanding of how LC- NE system activity is leveraged during both stress and pain to elicit stress-induced antinociception. This fellowship will provide me with intensive scientific training in cell-type selective in vivo optogenetics, in vivo fiber photometry, behavioral pharmacology, and immunohistochemistry. The combination of diverse experimental approaches provides excellent training potential and compounded with outstanding mentorship commitment from faculty at Washington University and external collaborators will help me achieve my career goal of becoming an independent academic and entrepreneurial scientist.