Abstract: Project 1, Adaptations of the brain in chronic pain with opioid exposure The current opioid epidemic is intimately linked with the clinical management of chronic pain. 15-20% of the US population suffers from the condition, and a sizable proportion of such patients are managed with opioids. Chronic back pain (CBP) is the most common chronic pain condition in the US. Research in the Apkarian lab has shown that brain addiction circuitry (mesocorticolimbic system), critical in opioid use disorder (OUD), is also causally linked to the development of chronic pain. Thus, an overarching hypothesis of this Project, and of our Center, is that opioid abuse liability and the development of chronic pain are interacting brain processes, and critical to explaining clinical outcomes of abuse liability and the loss/moderation of analgesic efficacy. Yet, there is virtually no human or rodent brain imaging evidence on the topic, and physiologic knowledge regarding the interaction between chronic pain, opioid analgesia and abuse liability is minimal. In this project, we will study brain reorganization and behavioral responses in chronic pain with opioid exposure, both in CBP and in a rat model of chronic pain (SNI). Aim 1a will study four groups: i) individuals with CBP managed with opioids and no signs of misuse (n=80); ii) patients with CBP and mild to moderate OUD (mOUD, n=80); iii) patients with CBP managed without opioids (n=25); and iv) healthy controls (n=25). We will track daily analgesic drug consumption and pain and craving reports over 1-2 weeks. In a single scan session, we collect brain anatomical and functional data (resting state fMRI, T1, DTI, ASL) to elucidate the neural correlates of pain, analgesia, and abuse liability. In Aim 1b, all participants from aim 1a will be assessed for motor, cognitive and emotional abilities (NIH Toolbox). Aim 1 results should distinguish between opioid resilient and vulnerable groups, and unravel the impact of opioid exposure on abilities and related brain maladaptations. In Aim 2a, 50% of the patients from groups i and ii (n=40/group) will be enrolled into a placebo-controlled drug withdrawal and re- exposure study. Opioid drug dispensing is delayed to provoke craving and/or increased pain, and participants are scanned during psychological withdrawal and after re-exposure. Re-exposure will involve their opioid drug, placebo, or sinemet and naproxen (DA+NSAID, a potential novel treatment), in a double-blind, randomized, cross-over design. Aim 2b will assess changes in motor, cognitive and emotional abilities at different phases of opioid withdrawal and re-exposure. Aim 2 data will differentiate circuitry for analgesia/hyperalgesia and OUD, test the effects of DA+NSAID on the brain, and the dependence of abilities on opioid states. Aim 3 will track brain activity and functional connectivity reorganization (rsfMRI and FDG PET), in SNI vs. sham rats, +/- morphine exposure. In some rats, brain imaging will be combined with viral chemogenetic manipulations to unravel circuit- and cell- type specific reorganization (for VTA, NAc, and dH). Aim 3 data will provide cross- species correspondences, linking human and rodent circuit adaptations, and establish in-vivo translational validity for the mouse in-vitro studies in Projects 2-4.