Raff CORT113176 Supplemental Stat Files 6-6-2025

The ability to avoid opioid use relapse is sexually dimorphic and challenging partly because of sleep disruption. The hypothalamic-pituitary adrenal (HPA) axis is a potential factor in this phenomenon making the glucocorticoid receptor (GR) a possible therapeutic target. We hypothesized that chronic administration of the novel GR receptor modulator CORT113176 during chronic sleep restriction (SR) and opioid abstinence would reveal important effects on the HPA axis giving insight into mechanisms of the interaction of SR and opioid abstinence. Using our rat model of persistent sleep loss during chronic opioid abstinence, we evaluated the effect of chronic CORT113176 administration on diurnal HPA axis dynamics and adrenal function, as well as the expression of critical mRNAs in the hypothalamus, pituitary, and adrenal in male and female rats. Unexpectedly, we found that CORT113176 acted as a direct agonist on plasma ACTH and corticosterone secretion, but an antagonist interacting with sleep restriction (SR) on hypothalamic and pituitary gene expression. These apparently conflicting effects were sexually dimorphic. We also found that CORT113176 suppressed the adrenal sensitivity to endogenous ACTH suggesting it was acting as an agonist on GR in the adrenal cortex. We conclude that the response of the HPA axis to CORT113176 during SR and opioid abstinence is not predictable because it can act as an antagonist and agonist in the brain and pituitary, and an agonist in the adrenal gland in a sexually dimorphic manner. Chronic SR differentially alters the way CORT113176 acts, modifying negative feedback in a sexually dimorphic manner.