Abstract Management of pain is a significant problem in the elderly, with the burden of chronic pain heavily tilted toward older adults. The high incidence of pain in the elderly has been suggested to be related to an increase in stress and underlying painful conditions throughout the life span (e.g., inflammation, surgery, disease, chemotherapy, and other stressful life events), which led the PI to her central hypothesis that nociceptor neuroplasticity in the elderly contributes to this increase in chronic pain. Hyperalgesic priming (priming) is a form of nociceptor neuroplasticity, a long- lasting change in nociceptor function, induced by trauma, inflammation, and stress. Therefore, it is of great interest to determine if the high incidence of pain in the elderly is related to priming, and whether it is caused by systemic inflammation, and if the treatments that reverse priming could provide a basis for the treatment of chronic pain in the elderly. In Aim (1) we propose to establish that aged rats express nociceptor plasticity (priming), the age at which priming develops, and if priming is associated with systemic inflammation (measuring the levels of circulating inflammatory cytokines) in F344xBN elderly rats. In Aim (2) we propose to identify mechanisms underlying priming in the elderly, determining the role of Type I and Type II priming in age- associated priming, and in which nociceptor population priming occurs. It is also known that age- related changes in mitochondria are associated with decline in mitochondrial function and, recently, mitochondrial dysfunction has been implicated in priming. Therefore, in Aim (2) we will also test the hypothesis that systemic inflammation and increased reactive oxygen species (ROS) production by mitochondrial dysfunction, result in priming. We will evaluate, by immunofluorescence, if ROS activity is greater in dorsal root ganglia (DRG) from aged rats, if modulating mitochondrial electron chain transport complex and scavenging a mitochondria- specific superoxide, in vivo, alleviates age-associated priming, and evaluate the oxygen consumption rate, ex vivo by the seahorse analyzer, to better understand how the main mitochondrial energy producing pathways are altered in association with age-associated priming, in DRG neurons. Since there are sex differences in pain syndromes in the elderly, and in priming, all the proposed experiments will be performed in both sexes, paving the way to more personalized management of pain in the elderly. The results of the proposed studies may be useful as a guide for the development of novel therapeutics for the prevention and treatment of chronic pain in the elderly.