Chronic postoperative pain induces contextual fear extinction dysfunction through hippocampal NMDAR/BDNF/TrkB signaling pathway in mice
Abstract Post-traumatic stress disorder (PTSD) is a common disorder in clinical practice, characterized by various manifestations, with fear extinction dysfunction being a typical one. Postoperative persistent pain, a form of chronic pain following surgical procedures, significantly affects patients...
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| Format: | Article |
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Nature Publishing Group
2025-06-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-025-03417-0 |
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| author | Jiawei Zhang Xiaoting Zheng Gaoyan Zhang Zhikun Cheng Yinuo Liu Lei Zhang Jiqian Zhang Xuesheng Liu Zhilai Yang |
| author_facet | Jiawei Zhang Xiaoting Zheng Gaoyan Zhang Zhikun Cheng Yinuo Liu Lei Zhang Jiqian Zhang Xuesheng Liu Zhilai Yang |
| author_sort | Jiawei Zhang |
| collection | DOAJ |
| description | Abstract Post-traumatic stress disorder (PTSD) is a common disorder in clinical practice, characterized by various manifestations, with fear extinction dysfunction being a typical one. Postoperative persistent pain, a form of chronic pain following surgical procedures, significantly affects patients’ quality of life. Clinical studies have demonstrated the comorbidity between chronic pain and PTSD; however, the molecular mechanisms underlying this comorbidity remain unclear. Researches have shown that brain-derived neurotrophic factor (BDNF) and N-methyl-D-aspartate glutamate receptors (NMDARs) are crucial in fear extinction dysfunction. Thus, we established a skin/muscle incision and retraction (SMIR) mice model to explore the roles of hippocampal NMDARs and BDNF signaling pathways in fear extinction following postoperative persistent pain. We found that SMIR mice exhibited contextual fear extinction dysfunction, potentially caused by a down-regulated NMDARs/ERK/CREB/BDNF signaling pathway and impaired synaptic plasticity in the hippocampus. Hippocampal injection of the NMDARs agonist NMDA promoted extinction learning and retrieval of extinction memory, activating the NMDARs/ERK/CREB/BDNF signaling pathway, and restoring lost dendritic spines. Simultaneous hippocampal administration of NMDA and the TrkB inhibitor ANA-12 promoted the learning process of fear extinction without enhancing the retrieval of extinction memory, while re-inducing dendritic spine loss. In summary, we conclude that postoperative persistent pain impairs synaptic plasticity by downregulating the NMDARs/ERK/CREB/BDNF signaling pathway, thereby inducing contextual fear extinction dysfunction. These findings may partially explain the mechanisms underlying the comorbidity between chronic pain and PTSD. |
| format | Article |
| id | doaj-art-52e65134a1c446d3856b4e3d185fff50 |
| institution | OA Journals |
| issn | 2158-3188 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj-art-52e65134a1c446d3856b4e3d185fff502025-08-20T02:37:36ZengNature Publishing GroupTranslational Psychiatry2158-31882025-06-0115111210.1038/s41398-025-03417-0Chronic postoperative pain induces contextual fear extinction dysfunction through hippocampal NMDAR/BDNF/TrkB signaling pathway in miceJiawei Zhang0Xiaoting Zheng1Gaoyan Zhang2Zhikun Cheng3Yinuo Liu4Lei Zhang5Jiqian Zhang6Xuesheng Liu7Zhilai Yang8Department of Anesthesiology, the First Affiliated Hospital of Anhui Medical UniversityDepartment of Anesthesiology, the Second Affiliated Hospital of Guangxi Medical UniversityDepartment of Anesthesiology, the First Affiliated Hospital of Anhui Medical UniversityDepartment of Anesthesiology, the First Affiliated Hospital of Anhui Medical UniversityDepartment of Anesthesiology, the First Affiliated Hospital of Anhui Medical UniversityDepartment of Anesthesiology, the First Affiliated Hospital of Anhui Medical UniversityDepartment of Anesthesiology, the First Affiliated Hospital of Anhui Medical UniversityDepartment of Anesthesiology, the First Affiliated Hospital of Anhui Medical UniversityDepartment of Anesthesiology, the First Affiliated Hospital of Anhui Medical UniversityAbstract Post-traumatic stress disorder (PTSD) is a common disorder in clinical practice, characterized by various manifestations, with fear extinction dysfunction being a typical one. Postoperative persistent pain, a form of chronic pain following surgical procedures, significantly affects patients’ quality of life. Clinical studies have demonstrated the comorbidity between chronic pain and PTSD; however, the molecular mechanisms underlying this comorbidity remain unclear. Researches have shown that brain-derived neurotrophic factor (BDNF) and N-methyl-D-aspartate glutamate receptors (NMDARs) are crucial in fear extinction dysfunction. Thus, we established a skin/muscle incision and retraction (SMIR) mice model to explore the roles of hippocampal NMDARs and BDNF signaling pathways in fear extinction following postoperative persistent pain. We found that SMIR mice exhibited contextual fear extinction dysfunction, potentially caused by a down-regulated NMDARs/ERK/CREB/BDNF signaling pathway and impaired synaptic plasticity in the hippocampus. Hippocampal injection of the NMDARs agonist NMDA promoted extinction learning and retrieval of extinction memory, activating the NMDARs/ERK/CREB/BDNF signaling pathway, and restoring lost dendritic spines. Simultaneous hippocampal administration of NMDA and the TrkB inhibitor ANA-12 promoted the learning process of fear extinction without enhancing the retrieval of extinction memory, while re-inducing dendritic spine loss. In summary, we conclude that postoperative persistent pain impairs synaptic plasticity by downregulating the NMDARs/ERK/CREB/BDNF signaling pathway, thereby inducing contextual fear extinction dysfunction. These findings may partially explain the mechanisms underlying the comorbidity between chronic pain and PTSD.https://doi.org/10.1038/s41398-025-03417-0 |
| spellingShingle | Jiawei Zhang Xiaoting Zheng Gaoyan Zhang Zhikun Cheng Yinuo Liu Lei Zhang Jiqian Zhang Xuesheng Liu Zhilai Yang Chronic postoperative pain induces contextual fear extinction dysfunction through hippocampal NMDAR/BDNF/TrkB signaling pathway in mice Translational Psychiatry |
| title | Chronic postoperative pain induces contextual fear extinction dysfunction through hippocampal NMDAR/BDNF/TrkB signaling pathway in mice |
| title_full | Chronic postoperative pain induces contextual fear extinction dysfunction through hippocampal NMDAR/BDNF/TrkB signaling pathway in mice |
| title_fullStr | Chronic postoperative pain induces contextual fear extinction dysfunction through hippocampal NMDAR/BDNF/TrkB signaling pathway in mice |
| title_full_unstemmed | Chronic postoperative pain induces contextual fear extinction dysfunction through hippocampal NMDAR/BDNF/TrkB signaling pathway in mice |
| title_short | Chronic postoperative pain induces contextual fear extinction dysfunction through hippocampal NMDAR/BDNF/TrkB signaling pathway in mice |
| title_sort | chronic postoperative pain induces contextual fear extinction dysfunction through hippocampal nmdar bdnf trkb signaling pathway in mice |
| url | https://doi.org/10.1038/s41398-025-03417-0 |
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