Project Summary Opioid use disorder (OUD) and obesity are major comorbid public health concerns that are increasing in national prevalence. OUD contributes to approximately 68% of all drug overdose deaths in the U.S., and obesity is a leading source of all-cause mortality. Patients diagnosed with obesity are also frequently diagnosed with chronic pain conditions and are more likely to be prescribed opioids. Further, obesity is highly prevalent among individuals with OUD, and is associated with higher risk for opioid overdose. This suggests that individuals with obesity have an increased risk both of being prescribed opioid analgesics and developing OUD; however, the physiological mechanisms that underlie these risks are not well understood. Obesity is linked to the consumption of high fat diets; however, it is not known if the risks related to OUD among patients diagnosed with obesity are due to this dietary history. This RCMI pilot project proposal investigates the impact of diet on the therapeutic, rewarding, and adverse effects of morphine, using behavioral and physiological assays in rats. Further, given recent evidence suggesting that high fat, low carbohydrate ketogenic diets might have beneficial effects for obesity, the proposed aims will also explore the effects of a ketogenic diet in addition to a low fat diet control condition. To explore the impact of diet on sensitivity of rats to morphine, animal models of the therapeutic effects of morphine (i.e., antinociception indexed via warm water tail withdrawal and von Frey paw withdrawal assays) and reward (i.e., conditioned place preference and behavioral sensitization) will be examined in Aim 1. Additionally, the adverse effects of morphine including constipation (decreased gastrointestinal transit) and dependence (as measured by the presence or absence of withdrawal symptoms following discontinuation or naloxone administration) will also be explored in Aim 2 to mimic the experiences of patients taking opioids chronically for pain management or recreational use. Finally, in Aim 3 this proposal will also evaluate changes in molecular markers within specific brain regions associated with reward processing, feeding, and nociception, to identify targets for future mechanism-driven assessments. These projects will provide a clear picture of the ways that dietary history might impact the therapeutic effectiveness of opioids, as well as their abuse liability, providing a translationally relevant assessment focused on two converging and increasing public health concerns: obesity and OUD. These aims will also involve the training of underrepresented minority scientists, including graduate and undergraduate students, and will serve to generate preliminary data that will be used for future NIH grant proposals. The PI, an early-stage investigator and underrepresented minority scientist, will also receive support through the Investigator Development Core within the RCMI U54 Center at the University of...