Abstract Chronic pain is a significant public health problem that costs society billions of dollars per year and causes great suffering in countless individuals. Opioid-based medications are among the most prescribed for various forms of chronic pain contributing to the current opioid epidemic. Recently, cannabis and cannabinoid compounds (e.g., Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD)) have been described as having pain-alleviating properties. While these cannabinoids, particularly the less psychoactive variant, CBD, may offer alternatives to opioid treatments for pain, few well-controlled studies demonstrate analgesic efficacy, especially for CBD. While it is still unclear if cannabinoids are good stand-alone options for treating pain, cannabinoids may act as useful opioid-sparing drugs, given the substantial overlap between opioid and cannabinoid receptors in reward- and pain-related pathways. Our proposed project will focus on a heuristic approach that incorporates fundamental pharmacology, novel operant behavioral assays of pain, and functional neuroimaging. The long-term goal of this research program is to establish novel approaches to treat chronic pain by maximizing analgesic efficacy and minimizing abuse liability. The objective of this proposal, which embodies the first step toward this long- term goal, is to determine how CBD modifies the effects of oxycodone (OXY), a commonly prescribed opioid analgesic, in the contexts of chronic pain and opioid self-administration. Our overarching hypothesis is that CBD and OXY will act synergistically to yield enhanced analgesic effects, and that CBD will attenuate the effects of pain on OXY self-administration. Two major specific aims will be investigated: (1) to determine how CBD interacts with OXY to reduce chronic operant pain behaviors; and (2) to determine the interacting effects of chronic pain, OXY self-administration, and CBD on analgesia, reinforcement, and dependence. We will assess the effects of preexisting pain on OXY self-administration, as well as the effects of preexisting OXY self- administration on pain. The latter goal is a particularly innovative aspect of this proposal. CBD-modulatory effects on pain and OXY self-administration will be evaluated under both conditions. Neuroimaging will be used across experiments to map and quantify changes in neural connectivity across reward and pain centers of the brain following the various drug treatments (CBD, OXY) and pain states (acute, chronic). Further, we will use clinically important and innovative pain-depressed behavioral assessments that accurately model pain in human subjects. The rationale for completing these studies is that by determining how CBD and OXY interact to affect pain and substance use, we will establish the necessary foundation for future efforts to develop effective analgesics with reduced abuse liability. We believe we are particularly well suited to undertake this project because we have a unified (an...