Nociceptor-localized KCC2 suppresses brachial plexus avulsion-induced neuropathic pain and related central sensitization
Abstract Lack in understanding of the mechanism on brachial plexus avulsion (BPA)-induced neuropathic pain (NP) is the key factor restricting its treatment. In the current investigation, we focused on the nociceptor-localized K+-Cl− cotransporter 2 (KCC2) to investigate its role in BPA-induced NP an...
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BMC
2025-01-01
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| Series: | Cell & Bioscience |
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| Online Access: | https://doi.org/10.1186/s13578-025-01354-5 |
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| author | Hang Xian Huan Guo Yuan-Ying Liu Sui-Bin Ma Rui Zhao Jian-Lei Zhang Hang Zhang Rou-Gang Xie Xu-Cheng Guo Jie Ren Sheng-Xi Wu Ceng Luo Rui Cong |
| author_facet | Hang Xian Huan Guo Yuan-Ying Liu Sui-Bin Ma Rui Zhao Jian-Lei Zhang Hang Zhang Rou-Gang Xie Xu-Cheng Guo Jie Ren Sheng-Xi Wu Ceng Luo Rui Cong |
| author_sort | Hang Xian |
| collection | DOAJ |
| description | Abstract Lack in understanding of the mechanism on brachial plexus avulsion (BPA)-induced neuropathic pain (NP) is the key factor restricting its treatment. In the current investigation, we focused on the nociceptor-localized K+-Cl− cotransporter 2 (KCC2) to investigate its role in BPA-induced NP and related pain sensitization. A novel mice model of BPA on the middle trunk (C7) was established, and BPA mice showed a significant reduction in mechanical withdrawal threshold of the affected fore- and hind- paws without affecting the motor function through CatWalk Gait analysis. Decreased expression of KCC2 in dorsal root ganglion (DRG) was detected through Western blot and FISH technology after BPA. Overexpression of KCC2 in DRG could reverse the hyperexcitability of DRG neurons and alleviate the pain of BPA mice synchronously. Meanwhile, the calcium response signal of the affected SDH could be significantly reduced through above method using spinal cord fiber photometry. The synthesis and release of brain-derived neurotrophic factor (BDNF) was also proved reduction through overexpression of KCC2 in DRG, which indicates BDNF can also act as the downstream role in this pain state. As in human-derived tissues, we found decreased expression of KCC2 and increased expression of BDNF and TrκB in avulsed roots of BPA patients compared with normal human DRGs. Our results indicate that nociceptor-localized KCC2 can suppress BPA-induced NP, and peripheral sensitization can be regulated to reverse central sensitization by targeting KCC2 in DRG at the peripheral level through BDNF signaling. The consistent results in both humanity and rodents endow great potential to future transformation of clinical practice. |
| format | Article |
| id | doaj-art-810ccb1786ac4ee4b8070f3bf0a95b49 |
| institution | Kabale University |
| issn | 2045-3701 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj-art-810ccb1786ac4ee4b8070f3bf0a95b492025-02-02T12:44:26ZengBMCCell & Bioscience2045-37012025-01-0115112110.1186/s13578-025-01354-5Nociceptor-localized KCC2 suppresses brachial plexus avulsion-induced neuropathic pain and related central sensitizationHang Xian0Huan Guo1Yuan-Ying Liu2Sui-Bin Ma3Rui Zhao4Jian-Lei Zhang5Hang Zhang6Rou-Gang Xie7Xu-Cheng Guo8Jie Ren9Sheng-Xi Wu10Ceng Luo11Rui Cong12Department of Orthopaedics, Xijing Hospital, Air Force Medical UniversityDepartment of Orthopaedics, Xijing Hospital, Air Force Medical UniversityDepartment of Neurobiology, School of Basic Medicine, Air Force Medical UniversityDepartment of Neurobiology, School of Basic Medicine, Air Force Medical UniversityDepartment of Orthopaedics, Xijing Hospital, Air Force Medical UniversityDepartment of Orthopaedics, Xijing Hospital, Air Force Medical UniversityDepartment of Orthopaedics, Xijing Hospital, Air Force Medical UniversityDepartment of Neurobiology, School of Basic Medicine, Air Force Medical UniversityDepartment of Orthopaedics, Xijing Hospital, Air Force Medical UniversityDepartment of Orthopaedics, Xijing Hospital, Air Force Medical UniversityDepartment of Neurobiology, School of Basic Medicine, Air Force Medical UniversityDepartment of Neurobiology, School of Basic Medicine, Air Force Medical UniversityDepartment of Orthopaedics, Xijing Hospital, Air Force Medical UniversityAbstract Lack in understanding of the mechanism on brachial plexus avulsion (BPA)-induced neuropathic pain (NP) is the key factor restricting its treatment. In the current investigation, we focused on the nociceptor-localized K+-Cl− cotransporter 2 (KCC2) to investigate its role in BPA-induced NP and related pain sensitization. A novel mice model of BPA on the middle trunk (C7) was established, and BPA mice showed a significant reduction in mechanical withdrawal threshold of the affected fore- and hind- paws without affecting the motor function through CatWalk Gait analysis. Decreased expression of KCC2 in dorsal root ganglion (DRG) was detected through Western blot and FISH technology after BPA. Overexpression of KCC2 in DRG could reverse the hyperexcitability of DRG neurons and alleviate the pain of BPA mice synchronously. Meanwhile, the calcium response signal of the affected SDH could be significantly reduced through above method using spinal cord fiber photometry. The synthesis and release of brain-derived neurotrophic factor (BDNF) was also proved reduction through overexpression of KCC2 in DRG, which indicates BDNF can also act as the downstream role in this pain state. As in human-derived tissues, we found decreased expression of KCC2 and increased expression of BDNF and TrκB in avulsed roots of BPA patients compared with normal human DRGs. Our results indicate that nociceptor-localized KCC2 can suppress BPA-induced NP, and peripheral sensitization can be regulated to reverse central sensitization by targeting KCC2 in DRG at the peripheral level through BDNF signaling. The consistent results in both humanity and rodents endow great potential to future transformation of clinical practice.https://doi.org/10.1186/s13578-025-01354-5Brachial plexus avulsionNeuropathic painCentral sensitizationPeripheral sensitizationKCC2BDNF |
| spellingShingle | Hang Xian Huan Guo Yuan-Ying Liu Sui-Bin Ma Rui Zhao Jian-Lei Zhang Hang Zhang Rou-Gang Xie Xu-Cheng Guo Jie Ren Sheng-Xi Wu Ceng Luo Rui Cong Nociceptor-localized KCC2 suppresses brachial plexus avulsion-induced neuropathic pain and related central sensitization Cell & Bioscience Brachial plexus avulsion Neuropathic pain Central sensitization Peripheral sensitization KCC2 BDNF |
| title | Nociceptor-localized KCC2 suppresses brachial plexus avulsion-induced neuropathic pain and related central sensitization |
| title_full | Nociceptor-localized KCC2 suppresses brachial plexus avulsion-induced neuropathic pain and related central sensitization |
| title_fullStr | Nociceptor-localized KCC2 suppresses brachial plexus avulsion-induced neuropathic pain and related central sensitization |
| title_full_unstemmed | Nociceptor-localized KCC2 suppresses brachial plexus avulsion-induced neuropathic pain and related central sensitization |
| title_short | Nociceptor-localized KCC2 suppresses brachial plexus avulsion-induced neuropathic pain and related central sensitization |
| title_sort | nociceptor localized kcc2 suppresses brachial plexus avulsion induced neuropathic pain and related central sensitization |
| topic | Brachial plexus avulsion Neuropathic pain Central sensitization Peripheral sensitization KCC2 BDNF |
| url | https://doi.org/10.1186/s13578-025-01354-5 |
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