Sex-specific transcriptional signatures of oxycodone persist during withdrawal and abstinence in the suprachiasmatic nucleus of heterogeneous stock rats

Opioid use disorder (OUD) is a major public health problem. Sleep and circadian disruptions are recognized as hallmarks of substance use disorders, often emerging during withdrawal and lasting into abstinence. Little is known about the impact of opioids on the brain's primary circadian pacemaker, the suprachiasmatic nucleus (SCN). We examined SCN transcriptomic changes in genetically diverse heterogeneous stock rats across different opioid physiological and behavioral states (naïve, oxycodone intoxication, acute withdrawal, and prolonged abstinence), alongside behavioral assessments. In females, intoxication and withdrawal altered pathways related to neurotransmission, circadian rhythms, and inflammation, while in males, changes involved immune regulation and DNA damage. During abstinence, females showed enrichment in stress-related pathways, particularly those involved in energy metabolism and neurotransmitter function, whereas males exhibited enrichment in pathways related to cellular detoxification and oxidative stress, suggesting lasting, sex-specific effects during withdrawal and abstinence. The highest proportion of sex-specific rhythmic differentially expressed genes were identified during abstinence compared to other states. Co-expression network analysis identified a module linked to synaptic signaling and another linked to ciliary function, which were positively and negatively associated with intoxication, respectively. The genes in the synaptic signaling module were positively correlated with addiction-related behaviors during abstinence, while the genes in the ciliary module inversely correlated with these behaviors during intoxication, linking opioid-induced alterations in the SCN to addiction-like phenotypes. These findings highlight the SCN as a dynamic, sex-specific target of opioid exposure and suggest that SCN alterations may contribute to long-term behavioral and physiological consequences of OUD.