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Acute and chronic stress differentially regulate pain via distinct ensembles in the paraventricular nucleus of hypothalamus

Molecular Psychiatry volume 31, pages 649–663 (2026)Cite this article

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Abstract

Stress impacts pain sensation and its development, but the underlying neural mechanisms are largely unclear. Using restraint stress models and complete Freund’s adjuvant-induced pain model in male mice, we demonstrated that acute restraint stress (ARS) induces analgesia in both naïve and pain states. In contrast, chronic restraint stress (CRS) enhances pain hypersensitivity in naïve states, prolongs pain duration, and promotes anxiodepressive symptoms in pain states. Notably, ARS and CRS distinctly activate neuronal ensembles in the paraventricular nucleus of the hypothalamus (PVN). Using the targeted recombination in active populations strategy and chemogenetics, we found that these neuronal ensembles mediate the effects of acute and chronic stress on pain sensation and development. Furthermore, through a two-vector strategy and chemogenetic approach, these neuronal ensembles appear to exert their effects via PVN-locus coeruleus and PVN-lateral septum projections, respectively. Overall, our findings offer novel insights into pain sensation and pain chronification, and may provide effective therapeutic strategies for clinical pain and emotional comorbidities.

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Fig. 1: Distinct impacts of acute and chronic stress on pain and associated emotional states.
Fig. 2: Activation of neuronal ensembles in the PVN by ARS and CRS.
Fig. 3: The influence of TRAP-ARS neurons in the PVN on pain and associated emotional states.
Fig. 4: The impact of TRAP-CRS neurons in the PVN on pain and associated emotional states.
Fig. 5: The effects of ARS were mediated by the PVN-LC projection.
Fig. 6: The effects of CRS were mediated by the PVN-LS projection.

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Data availability

All data to support the conclusions are present in the paper or supplementary materials. Because the raw data are huge and presented in diverse formats, the raw data are available from the corresponding author upon request.

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Acknowledgements

We would like to acknowledge Prof. Hongxing Zhang (Xuzhou Medical University, Xuzhou, China) for the guidance in use of transgenic mice, and Drs. Chunhua Zhang, Ruyi Zhang, Huiwen Zhang, Yaxi Zhang, Ying Liang and Ran Hu (Core Facility of The First Affiliated Hospital of Nanjing Medical University, Nanjing, China) for technical support.

Funding

This study was supported by grants from the National Natural Science Foundation of China (81974171 and 82271254 to C.Y., 81720108013, 82293641 and 82130033 to J.L.C., 82401453 to S.H., 82191279 to C.H., 82301444 to Q.Z., 82201420 to D.W., 82401469 to X.Z.), the Sci-Tech Innovation 2030-Major Project (2021ZD0203100 to J.L.C.), Innovative and Entrepreneurial Team of Jiangsu Province (JSSCTD202144 to C.Y.), Jiangsu Basic Research Programs (BK20243035 to J.L.C.), Natural Science Foundation of Jiangsu Province (BK20240054 to C.Y., BK20230741 to S.H., BK20210975 to C.H.), Excellent postdoctoral program of Jiangsu Province (2023ZB599 to S.H.), China Postdoctoral Science Foundation (2023M731409 to S.H., 2023M741467 to Q.Z.) and Wu Jieping Medical Foundation (310.6750.2024-15-82 to S.H., 320.6750.2024-15-81 to Q.Z.).

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  1. These authors contributed equally: Suwan Hu, Jingyao Huang, Qi Zhang.

Authors and Affiliations

  1. Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

    Suwan Hu, Jingyao Huang, Qi Zhang, Siqi Yang, Zifeng Wu, Yuanyuan Wang, Xinying Zhang, Di Wang, Yawei Ji, Haoran Wang, Changmao Zhu, Jian-Jun Yang, Cunming Liu, Chaoli Huang & Chun Yang

  2. Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China

    Jun-Li Cao

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Contributions

SH, QZ, JJY, CL, CH, JLC, and CY initiated and designed the research. SH, JH, CH and CY wrote the manuscript. SH, JH, QZ, CH, SY, ZW, YW, XZ, DW, YJ, HW, and CZ conducted experiments and analyzed the data. All the authors approved the submission.

Corresponding authors

Correspondence to Chaoli Huang, Jun-Li Cao or Chun Yang.

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The authors declare no competing interests.

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All experimental manipulations on mice were approved by the Institutional Animal Care and Use Committee of Nanjing Medical University (Registration number: No. IACUC-2307021) and were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. No human studies were performed. All authors read and approved the final manuscript.

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Hu, S., Huang, J., Zhang, Q. et al. Acute and chronic stress differentially regulate pain via distinct ensembles in the paraventricular nucleus of hypothalamus. Mol Psychiatry 31, 649–663 (2026). https://doi.org/10.1038/s41380-025-03144-4

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