Veterans have more severe chronic pain than non-veteran patients and are reportedly twice as likely to die of an opioid overdose in attempts to find relief. These consequences lie behind the critical need to determine brain alterations causing chronification of pain that are too often progressing to the anxiety and depression responsible for the increased suicide rate among our veterans. Better understanding of underlying mechanisms driving chronic pain is imperative to development of more effective non-opioid treatment approaches for chronic pain. During the currently funded VA Merit grant period, we performed manganese enhanced MRI (MEMRI) studies using our experimental chronic neuropathic pain model. MEMRI allows visualization of neural activation in the small rodent brain using a 7T Bruker MRI scanner. As in clinical fMRI studies, we identified specific limbic emotional brain regions overactivated by chronic pain in addition to activation of the pain circuitry itself. It is apparent in our Preliminary Data histological follow-up that ongoing cellular stress is occurring in limbic brain circuitry. Due to the neuronal overactivation, pathophysiological alterations in limbic brain pain circuitry include increased expression of cellular stress biomarkers and altered expression of protective autophagy biomarkers. Autophagy is defined as the ongoing cellular protective mechanisms removing damaged and misfolded proteins generated during cellular stress. Disrupted autophagy homeostasis that produces autophagic dysfunction adversely affects cell function and eventually viability. The goal of the proposed studies is to examine whether boosting cell protective autophagy mechanisms can not only reduce neuropathic pain chronification related behaviors but can conceivably reduce the related brain pain circuitry neuropathology. Our studies performed at 8-10 weeks after induction in our chronic neuropathic pain model allows salient clinical relevance. We will test whether cellular stress/autophagy mechanisms are related to the noradrenergic alpha 1 receptor (NAα1R) signaling we identified as a primary chronic pain generator in the previous Merit grant funding period. The NAα1R blocker we will test is the clinical therapeutic doxazosin that might also be used as PTSD therapy. Doxazosin is longer lasting than the prazosin we tested in the same model in the previous grant period. Prazosin reduced chronic pain and aversive anxiety and depression related behaviors we observed through the 10 week time points (see Progress Report). We will test efficacy of doxazosin to reduce chronic neuropathic pain induced mechanical hypersensitivity, and perform anxiety and depression related behavioral assays. Comparisons of the efficacy of doxazosin can be made to prazosin and the effects of cellular stress inhibitors/autophagy enhancers. We find based on our recently completed MEMRI study that overactivation in specific limbic cortical regions after 10 weeks of ongoing neurop...