A neural circuit for sex-dependent conditioned pain hypersensitivity in mice
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...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58851-x |
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| author | Mingjun Zhang Ziyun Ni Jun Ma An Liu Ying Liu Qianqian Lou Wan-Ying Dong Zhi Zhang Juan Li Peng Cao |
| author_facet | Mingjun Zhang Ziyun Ni Jun Ma An Liu Ying Liu Qianqian Lou Wan-Ying Dong Zhi Zhang Juan Li Peng Cao |
| author_sort | Mingjun Zhang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-3567e27a244e4ed69b3bcd42949e6d42 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-3567e27a244e4ed69b3bcd42949e6d422025-08-20T02:28:10ZengNature PortfolioNature Communications2041-17232025-04-0116111610.1038/s41467-025-58851-xA neural circuit for sex-dependent conditioned pain hypersensitivity in miceMingjun Zhang0Ziyun Ni1Jun Ma2An Liu3Ying Liu4Qianqian Lou5Wan-Ying Dong6Zhi Zhang7Juan Li8Peng Cao9Department 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment of Physiology, School of Basic Medical Sciences, Anhui Medical UniversityDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaAbstract 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.https://doi.org/10.1038/s41467-025-58851-x |
| spellingShingle | Mingjun Zhang Ziyun Ni Jun Ma An Liu Ying Liu Qianqian Lou Wan-Ying Dong Zhi Zhang Juan Li Peng Cao A neural circuit for sex-dependent conditioned pain hypersensitivity in mice Nature Communications |
| title | A neural circuit for sex-dependent conditioned pain hypersensitivity in mice |
| title_full | A neural circuit for sex-dependent conditioned pain hypersensitivity in mice |
| title_fullStr | A neural circuit for sex-dependent conditioned pain hypersensitivity in mice |
| title_full_unstemmed | A neural circuit for sex-dependent conditioned pain hypersensitivity in mice |
| title_short | A neural circuit for sex-dependent conditioned pain hypersensitivity in mice |
| title_sort | neural circuit for sex dependent conditioned pain hypersensitivity in mice |
| url | https://doi.org/10.1038/s41467-025-58851-x |
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