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Background: Alcohol use disorder (AUD) is a complex psychiatric disease characterized by high alcohol intake as well as hyperkatifeia and hyperalgesia during withdrawal. A role for Sigma‐1 receptors (Sig‐1Rs) in the rewarding and reinforcing effects of alcohol has started to emerge in recent years, as rat studies have indicated that Sig‐1R hyperactivity may result in excessive alcohol drinking. Sig‐1R studies in mice are very scarce, and its potential role in alcohol‐induced hyperalgesia is also unknown. Methods: In this study, we investigated the role of Sig‐1R in alcohol drinking and associated hyperalgesia in male mice, using an intermittent access 2‐bottle choice model of heavy drinking. Results: The Sig‐1R antagonist BD‐1063 was found dose dependently to reduce both alcohol intake and preference, without affecting either water or sucrose intake, suggesting that the effects are specific for alcohol. Notably, the ability of BD‐1063 to suppress ethanol intake correlated with the individual baseline levels of alcohol drinking, suggesting that the treatment was more efficacious in heavy drinking animals. In addition, BD‐1063 reversed alcohol‐induced hyperalgesia during withdrawal, assessed using an automatic Hargreaves test, without affecting thermal sensitivity in alcohol‐naïve animals or locomotor activity in either group. Conclusions: These data show that Sig‐1R antagonism dose‐dependently reduced ethanol consumption in heavy drinking mice as well as its efficacy in reducing alcohol‐induced hyperalgesia. These findings provide a foundation for the development of novel treatments for AUD and associated pain states. [ABSTRACT FROM AUTHOR]

Opioid misuse, addiction, and associated overdose deaths remain global public health crises. Despite the tremendous need for pharmacological treatments, current options are limited in number, use, and effectiveness. Fundamental leaps forward in our understanding of the biology driving opioid addiction are needed to guide development of more effective medication-assisted therapies. This Review focuses on the omics-identified biological features associated with opioid addiction. Recent GWAS have begun to identify robust genetic associations, including variants in OPRM1, FURIN, and the gene cluster SCAI/PPP6C/RABEPK. An increasing number of omics studies of postmortem human brain tissue examining biological features (e.g., histone modification and gene expression) across different brain regions have identified broad gene dysregulation associated with overdose death among opioid misusers. Drawn together by meta-analysis and multi-omic systems biology, and informed by model organism studies, key biological pathways enriched for opioid addiction-associated genes are emerging, which include specific receptors (e.g., GABAB receptors, GPCR, and Trk) linked to signaling pathways (e.g., Trk, ERK/MAPK, orexin) that are associated with synaptic plasticity and neuronal signaling. Studies leveraging the agnostic discovery power of omics and placing it within the context of functional neurobiology will propel us toward much-needed, field-changing breakthroughs, including identification of actionable targets for drug development to treat this devastating brain disease. [ABSTRACT FROM AUTHOR]