Adrenal remodeling encodes stress axis memory to shape fentanyl seeking

The hypothalamic-pituitary-adrenal (HPA) axis is implicated in substance use disorders, yet the features of this circuit that contribute to addiction vulnerability remain unclear. Here, we show that fentanyl engages with different components of the HPA axis, and this engagement varies across timescales. Within minutes, fentanyl activated corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (PVNCRH) and transiently increased adrenocorticotropic hormone (ACTH) levels. Hours to days later, fentanyl suppressed PVN activity, reduced adrenal size, and impaired corticosterone release. Conversely, ACTH-induced adrenal hypertrophy, increased corticosterone, suppressed fentanyl-evoked PVNCRH activity, and elevated fentanyl-seeking behavior. These findings identify adrenal remodeling as a physiological record of stress history that shapes neuroendocrine and behavioral responses to fentanyl, mechanistically linking stress and addiction while revealing treatment targets for opioid dependence.