Role of a novel dynorphinergic extended amygdala circuit in pain- and fentanyl abstinence- facilitated alcohol drinking

PROJECT SUMMARY Chronic pain is a leading cause of disability worldwide, drastically decreases quality of life, and can drive the development and maintenance of both alcohol (AUD) and opioid (OUD) use disorders. Both alcohol and opioid use are reported for pain relief, and co-morbid use of both substances is increasingly common, increasing the negative effects of either substance used in isolation. Currently, there is limited research, preclinical or clinical, regarding co-occurring alcohol and opioid use is the context of chronic pain. The kappa opioid receptor (KOR) and its endogenous ligand dynorphin (DYN) is an endogenous opioid system that is widely expressed throughout the brain and heavily implicated in alcohol drinking, opioid seeking, and pain chronification. Our lab has recently identified a novel circuit of nucleus accumbens (NAc) projecting dynorphinergic central amygdala (CeA) neurons that is modulated by persistent pain and contributes to negative affect. However, this circuit has not been investigated in alcohol or opioid use. Here, I propose to test the role of DYN CeA-NAc signaling in 1) binge-like alcohol drinking during persistent pain and protracted fentanyl abstinence, 2) pain avoidance-like behavior and the effects of alcohol on this behavior, and 3) the effects of binge alcohol on reinstatement of fentanyl seeking behavior. I will use a combination of behavioral, photometric, and chemogenetic techniques to test the overarching hypothesis that persistent pain and fentanyl abstinence inhibit a novel dynorphinergic CeA-NAc circuit to drive binge-like alcohol drinking and subsequent effects on cognitive/motivational pain behaviors and reinstatement of fentanyl-seeking in a sex-dependent manner. The proposed work will fill a gap in our knowledge regarding polysubstance use in the context of chronic pain and provide valuable training to a promising young alcohol neuroscientist.