How distress alters opioid drug effects and abuse liability

As the opioid epidemic escalates, we must ask: why are opioids so addictive? Non-human animal research links addiction with the powerful relief opioids can offer to animals in distress. In humans, epidemiological and clinical studies converge upon social stressors and a poor social support network as key risk factors for addiction. Despite this, it is currently unknown how pre-drug distress might alter opioid drug effects. Tremendous resources are dedicated to charting how people feel after taking a drug, sidestepping the potentially profound influence of how people feel before they take the drug. Here, I will turn the current approach on its head. Using acute social distress induction before morphine administration in healthy humans, I will create a human model to determine the psychological, physiological and brain underpinnings of how social stressors increase opioids’ abuse liability. First, I will test the hypothesis that pre-drug distress enhances drug wanting (self-administration) but not drug liking (self-report) compared to drug effects in a control condition. Second, I will use opioid blockade to confirm or falsify the hypothesis that opioid drugs ‘hijack’ brain mechanisms underpinning social support. Third, I will determine to what extent opioid drug effects are dopamine-dependent by blocking dopamine before morphine administration. I will also apply computational modelling and functional imaging to elucidate the underlying brain mechanisms. Thus, the proposal offers a powerful new methodology for resolving hotly debated questions on the independent contributions of opioids and dopamine for reward and abuse liability. In sum, the project aims to achieve a breakthrough in our understanding of how a pre-drug social distress state can alter opioid drug mechanisms. The mechanistic understanding arising from this project could have profound implications for science, as well as for clinical care and new policies designed to contain the opioid epidemic.