Heroin self-administration induces sex-specific SUMOylation at early abstinence

Abstract

Introduction: Opioid use disorder, particularly heroin use disorder (HUD), is a major medical challenge, marked by severe withdrawal symptoms and a high risk of relapse. Heroin abuse leads to severe withdrawal and high relapse rates, with neuroadaptations contributing to relapse. Sex-specific differences in heroin-induced neuroadaptations are poorly understood, limiting effective therapies. Posttranslational modifications (PTMs), such as SUMOylation, play a key role in regulating protein function and neuroplasticity. SUMOylation attaches SUMO proteins to lysine residues, altering protein activity and influencing addiction mechanisms. Understanding sex-specific PTMs like SUMOylation could reveal new therapeutic targets for heroin addiction.Methods: We employed a novel SUMO Capture Assay combined with liquid chromatography-mass spectrometry (LC-MS) to investigate SUMOylation in the nucleus accumbens (NAc) of rats subjected to heroin self-administration. Male and female rats underwent contingent heroin administration followed by a period of early abstinence. Global SUMOylation levels and specific SUMOylated proteins were analyzed to assess sex-specific differences in SUMOylation patterns.Results: Our analysis revealed significant sex-specific alterations in protein SUMOylation during early abstinence, notably, males exhibited selective SUMOylation of specific protein targets, including TCP-1η, a critical chaperone involved in protein folding. These findings suggest that SUMOylation may underlie sex-specific neurobiological responses to heroin abstinence and contribute to the persistent neuroadaptations associated with HUD.Conclusion: Preliminary studies show sex-specific changes in protein SUMOylation within the nucleus accumbens (NAc) during early abstinence from heroin self-administration. SUMO-Capture-LC/MS analysis revealed that SUMOylation occurs selectively in males on specific proteins, including TCP-1η, an important chaperone needed for protein folding. These findings suggest that SUMOylation may contribute to sex-specific neurobiological responses during heroin abstinence, highlighting potential targets for further investigation