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  3. A neural circuit for sex-dependent conditioned pain hypersensitivity in mice

A neural circuit for sex-dependent conditioned pain hypersensitivity in mice

  • Nat Commun. 2025 Apr 17;16(1):3639. doi: 10.1038/s41467-025-58851-x.
Mingjun Zhang # 1,  Ziyun Ni # 1,  Jun Ma # 1,  An Liu # 2,  Ying Liu 1,  Qianqian Lou 1,  Wan-Ying Dong 1,  Zhi Zhang 3 4 5,  Juan Li 6,  Peng Cao 7 8
Affiliations

Affiliations

  • 1 Department of Anesthesiology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China.
  • 2 Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230022, China.
  • 3 Department of Anesthesiology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China. zhizhang@ustc.edu.cn.
  • 4 Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230022, China. zhizhang@ustc.edu.cn.
  • 5 Department of Biophysics and Neurobiology, CAS Key laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, 230026, China. zhizhang@ustc.edu.cn.
  • 6 Department of Anesthesiology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China. huamuzi1999@hotmail.com.
  • 7 Department of Anesthesiology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China. pengcao@ustc.edu.cn.
  • 8 Department of Biophysics and Neurobiology, CAS Key laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, 230026, China. pengcao@ustc.edu.cn.
  • # Contributed equally.
PMID: 40240334 DOI: 10.1038/s41467-025-58851-x
Abstract

The neural mechanisms underlying sex-specific pain, in which males and females exhibit distinct responses to pain, remain poorly understood. Here we show that in a mouse model of male-specific pain hypersensitivity response to pain conditioning environments (contextual pain hypersensitivity model), elevated free-testosterone leads to hyperactivity of glutamatergic neurons in the medial preoptic area (GlumPOA) through activation of Androgen Receptor signaling, which in turn induces contextual pain hypersensitivity in male mice. Although not observed in naïve female mice, this pain phenotype could be induced in females via chronic administration of testosterone propionate. In addition, GlumPOA neurons send excitatory inputs to GABAergic neurons in the ventrolateral periaqueductal gray (GABAvlPAG) that are required for contextual pain hypersensitivity. Our study thus demonstrates that testosterone/Androgen Receptor signaling enhances GlumPOA → GABAvlPAG pathway activity, which drives a male-specific contextual pain hypersensitivity, providing insight into the basis of sexually dimorphic pain response.

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