Identifying Novel Therapeutic Approaches for Individual Symptoms of Alcohol Use Disorder

Abstract

Alcohol use disorder (AUD) is a multi-symptomatic disorder which presents a continued challenge and burden to healthcare worldwide. While current Food and Drug Administration (FDA) approved treatments of AUD address some symptoms, they do not address others, notably alcohol dependence-associated pain; additionally, the existing treatments have limited effectiveness, leaving subpopulations of AUD patients underserved. Our work examined and summarized the current research on alcohol dependence-associated pain and provided a comprehensive overview of techniques to quantify nociception in rodent models, in the context of AUD research. We then examined different potential nociceptive signaling pathways for their involvement in dependence associated-pain using the chronic intermittent ethanol vapor (CIE) mouse model. We found that the alcohol dependence associated-pain mechanism is distinct from other mechanisms of chronic pain and that it is independent of endocannabinoid signaling pathways. As our prior work found association between plasma levels of pro-inflammatory lipid 15-Hydroxyeicosatetraenoic acid (15(S)-HETE) in AUD patients with their alcohol craving, and the 15-lipoxygenase (15-LOX) signaling pathway is involved in the development of chronic pain, we examined the relationship between this pathway and various symptoms of AUD. We found that 15-LOX signaling contributes to the escalation of alcohol intake characteristic of alcohol dependence and the development of craving-like behaviors. Overall, our findings highlight the importance and uniqueness of the different mechanisms that underlie different symptoms of AUD, with alcohol dependence associated-pain having a distinct mechanism different from other chronic pain mechanisms and powerfully implicate the 15-LOX signaling pathway in escalation of alcohol intake and craving.