Adrenal remodeling encodes stress axis memory to shape fentanyl seeking
Abstract
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.
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BibTeX
@misc{maretich2026adrenal,
title = {{Adrenal remodeling encodes stress axis memory to shape fentanyl seeking}},
author = {P. Maretich and T. M. Cannon and T. Milo and N. Pagane and E. J. Frey and F. Choe and E. Vargas Paniagua and R. Leomi and S. Machen and K. Nagao and H. S. Wong and S. L. Prescott and K. J. Ressler and P. Anikeeva},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.20.760432},
url = {https://www.biorxiv.org/content/10.64898/2026.10.20.760432v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Adrenal remodeling encodes stress axis memory to shape fentanyl seeking
AU - P. Maretich
AU - T. M. Cannon
AU - T. Milo
AU - N. Pagane
AU - E. J. Frey
AU - F. Choe
AU - E. Vargas Paniagua
AU - R. Leomi
AU - S. Machen
AU - K. Nagao
AU - H. S. Wong
AU - S. L. Prescott
AU - K. J. Ressler
AU - P. Anikeeva
PY - 2026
DA - 2026/10/20
PB - bioRxiv
DO - 10.64898/2026.10.20.760432
UR - https://www.biorxiv.org/content/10.64898/2026.10.20.760432v1
AB - 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.
ER -