---
title: "Adrenal remodeling encodes stress-axis memory that alters fentanyl seeking"
id: "biorxiv-0-adrenal-remodeling-encodes-stress-axis-memory-to-shape-fentanyl-seeking"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-0-adrenal-remodeling-encodes-stress-axis-memory-to-shape-fentanyl-seeking"
content_type: "clinical_feed_article"
specialty: "General"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.10.20.760432v1?rss=1"
published_at: "2026-10-25T10:35:09.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Adrenal remodeling encodes stress-axis memory that alters fentanyl seeking
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-0-adrenal-remodeling-encodes-stress-axis-memory-to-shape-fentanyl-seeking
- **Specialty:** [General](https://medichelpline.com/clinical-feed/general.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.10.20.760432v1?rss=1)
- **Published At:** 2026-10-25T10:35:09.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The preprint investigated interactions between **fentanyl** and the **HPA axis**, reporting rapid and delayed neuroendocrine effects that correlate with fentanyl-seeking behavior. - Within minutes, investigators reported activation of paraventricular nucleus corticotropin-releasing hormone neurons (**PVNCRH**) and a transient rise in **ACTH**. - On a timescale of hours to days, the study team observed suppressed PVN activity, reduced **adrenal** gland size, and impaired **corticosterone** release after fentanyl exposure. - In contrast, pharmacologic or physiologic **ACTH** stimulation produced adrenal hypertrophy and elevated corticosterone; this manipulation also suppressed fentanyl-evoked **PVNCRH** activity and increased fentanyl-seeking behavior. - Data indicated that structural and functional changes in the adrenal gland function as a persistent record of prior stress-axis engagement, linking peripheral endocrine remodeling to subsequent neural and behavioral responses to opioids. - Authors noted that these results provide mechanistic connections between stress history and addiction vulnerability and suggest that the adrenal may be a target for interventions to modify opioid-seeking circuits. - The source did not report detailed methods, dosing regimens, sample sizes, timepoints beyond the broad minutes-to-days description, or specific behavioral assay protocols in the abstract.
## Clinical Analysis & Structured Key Points
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Pema Maretich PhD 1 Massachusetts Institute of Technology; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Pema%2BMaretich%2B%3Cspan%2Bclass%3D%22nlm-suffix%22%3EPhD%3C/span%3E "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Maretich%20P&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3APema%2BMaretich%2BPhD) Taylor M Cannon PhD 1 Massachusetts Institute of Technology; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Taylor%2BM%2BCannon%2B%3Cspan%2Bclass%3D%22nlm-suffix%22%3EPhD%3C/span%3E "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Cannon%20TM&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ATaylor%2BM%2BCannon%2BPhD) Tomer Milo PhD 2 Ragon Institute of Mass General Brigham, MIT, and Harvard; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Tomer%2BMilo%2B%3Cspan%2Bclass%3D%22nlm-suffix%22%3EPhD%3C/span%3E "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Milo%20T&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ATomer%2BMilo%2BPhD) Nicole Pagane 2 Ragon Institute of Mass General Brigham, MIT, and Harvard; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Nicole%2BPagane%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Pagane%20N&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ANicole%2BPagane%2B) Ethan J Frey 1 Massachusetts Institute of Technology; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Ethan%2BJ%2BFrey%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Frey%20EJ&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AEthan%2BJ%2BFrey%2B) Faith Choe 1 Massachusetts Institute of Technology; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Faith%2BChoe%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Choe%20F&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AFaith%2BChoe%2B) Emmanuel Vargas Paniagua 1 Massachusetts Institute of Technology; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Emmanuel%2BVargas%2BPaniagua%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Vargas%20Paniagua%20E&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AEmmanuel%2BVargas%2BPaniagua%2B) Rebecca Leomi 1 Massachusetts Institute of Technology; 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Harvard Medical School * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Kerry%2BJ%2BRessler%2B%3Cspan%2Bclass%3D%22nlm-suffix%22%3EMD%2C%2BPhD%3C/span%3E "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Ressler%20KJ&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AKerry%2BJ%2BRessler%2BMD%252C%2BPhD) Polina Anikeeva PhD 1 Massachusetts Institute of Technology; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Polina%2BAnikeeva%2B%3Cspan%2Bclass%3D%22nlm-suffix%22%3EPhD%3C/span%3E "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Anikeeva%20P&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3APolina%2BAnikeeva%2BPhD) * For correspondence: anikeeva@mit.edu * [Abstract](https://www.biorxiv.org/content/10.64898/2026.10.20.760432v1)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_art/node:5901256/1) * [Info/History](https://www.biorxiv.org/content/10.64898/2026.10.20.760432v1.article-info)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_info/node:5901256/1) * [Metrics](https://www.biorxiv.org/content/10.64898/2026.10.20.760432v1.article-metrics)[](https://www.biorxiv.org/panels_ajax_tab/article_tab_metrics/node:5901256/1) * [Supplementary material](https://www.biorxiv.org/content/10.64898/2026.10.20.760432v1.supplementary-material)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_data/node:5901256/1) * [ Preview PDF](https://www.biorxiv.org/content/10.64898/2026.10.20.760432v1.full.pdf+html)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_pdf/node:5901256/1) ![Loading](https://www.biorxiv.org/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif) ## 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. ### Competing Interest Statement In the past 2 years, K.J.R has performed scientific consultation for Seaport, Leal, Transcend Therapeutics and Jazz Pharma; serves on Scientific Advisory Boards for Sage, Senseye, and the Brain Research Foundation, and has received sponsored research support from Compass Pathways and Ono Pharmaceuticals, none of which is related to the current work. P.A. is a co-founder and scientific advisor for Neurobionics Inc., an activity distinct and separate from the current work. Other authors declare that they have no competing interests. ## Funder Information Declared McGovern Institute for Brain Research National Institutes of Health and National Institute for Complementary and Integrative Health, Pioneer Award DP1-AT011991 MathWorks (United States), https://ror.org/01n8qtk87, Fellowship Janet and Sheldon Razin, Fellowship NIH, NRSA F32 Fellowship, GRFP Fellowship Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a [CC-BY 4.0 International license](http://creativecommons.org/licenses/by/4.0/). bioRxiv and medRxiv thank the following for their generous financial support: > The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The University of Edinburgh, University of Washington, and Vrije Universiteit Amsterdam. [Donate to openRxiv ](https://www.zeffy.com/en-US/donatio
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