REVISED NEW CORT113176 STATS 5-28-2025

The ability to avoid relapse to opioid use is sexually dimorphic and challenging partly because of the co-morbid sleep disruption that occurs. The hypothalamic-pituitary adrenal (HPA) axis is thought to be a factor in this phenomenon making the glucocorticoid receptor (GR) a potential therapeutic target. We hypothesized that the 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 hypothalamic PVN and pituitaries in male and female rats. Unexpectedly, we found that CORT113176 acted more like a direct agonist on plasma ACTH, and hence 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 surprisingly 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 by sex or sleep state because it can act both as an antagonist and agonist in the brain and pituitary, and an agonist in the adrenal gland in a sexually dimorphic manner.