Alcohol-Cannabinoid System Interactions in the Context of Pain and AUD

Abstract Alcohol use disorder (AUD) affects more than 10% of the United States population. AUD is a psychiatric disorder characterized by escalated alcohol drinking and the emergence of profound negative affective states, including persistent pain. Alcohol is also known for its analgesic effects, although excessive use facilitates pain sensitivity (or hyperalgesia) during withdrawal. While chronic pain affects over 20% of the global population and contributes to the development and severity of both psychiatric illness and AUD, effective pharmacological treatments for these conditions remain very limited. In recent years, many people have turned to cannabis for management of chronic pain and various negative emotional symptoms associated with mental illness. However, there is a significant gap in knowledge regarding the analgesic efficacy of primary cannabis constituents in the context of alcohol dependence and how use may either mitigate or worsen the risk of substance use disorders. Specifically, delta-9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, may offer a promising avenue for pain management, a common cause of excessive drinking in individuals with AUD. From a neurobiological perspective, the extended amygdala (EA) plays an important role in stress- and pain-related components of AUD and is a site where the endocannabinoid (eCB) system appears critical for modulating the reinforcing effects of ethanol and transition to dependence. Our previous preclinical work has shown a functional role for the central amygdala (CeA), a constituent of the EA, as a key brain region underlying hyperalgesia and escalation of alcohol drinking in alcohol-dependent animal models. Our preliminary data indicate an eCB system dysregulation generated by chronic alcohol exposure, which may promote the use of alcohol and imply the therapeutic efficacy of cannabis/THC in individuals suffering from AUD and AUD-related hyperalgesia. The main research objective of the current proposal is to investigate the intricate interplay between the endocannabinoid system, pain, and alcohol use. The studies outlined in this F30 training proposal incorporate both animal modeling and clinical investigation to examine the predictions that: 1) delta-9-THC administration alleviates hyperalgesia and reduces escalated alcohol self-administration in alcohol-dependent male and female rats, and 2) increased cannabis use is associated with overall reductions in pain symptoms and at-risk alcohol use in men and women. This proposal will provide a promising future physician-scientist with vital research training to become an independent scientist in the field of alcohol and clinical neuroscience research.