Netrin-1 Role in Nociceptive Neuron Sprouting through Activation of DCC Signaling in a Rat Model of Bone Cancer Pain
Background: Bone cancer pain (BCP) is a common primary or metastatic bone cancer complication. Netrin-1 plays an essential role in neurite elongation and pain sensitization. This study aimed to determine the role of netrin-1 from the metastatic bone microenvironment in BCP development and identify t...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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IMR Press
2024-02-01
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| Series: | Journal of Integrative Neuroscience |
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| Online Access: | https://www.imrpress.com/journal/JIN/23/3/10.31083/j.jin2303047 |
| _version_ | 1797238643062996992 |
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| author | Zhihao Gong Yuxin Zhang Wei Wang Xin Li Kai Wang Xingji You Jingxiang Wu |
| author_facet | Zhihao Gong Yuxin Zhang Wei Wang Xin Li Kai Wang Xingji You Jingxiang Wu |
| author_sort | Zhihao Gong |
| collection | DOAJ |
| description | Background: Bone cancer pain (BCP) is a common primary or metastatic bone cancer complication. Netrin-1 plays an essential role in neurite elongation and pain sensitization. This study aimed to determine the role of netrin-1 from the metastatic bone microenvironment in BCP development and identify the associated signaling pathway for the strategy of BCP management. Methods: The rat BCP model was established by intratibial implantation of Walker 256 cells. Von Frey filaments measured the mechanical pain threshold. Movement-induced pain was assessed using limb use scores. Expressions of associated molecules in the affected tibias or dorsal root ganglia (DRG) were measured by immunofluorescence, immunohistochemistry, real-time quantitative polymerase chain reaction, or western blotting. Transduction of deleted in colorectal cancer (DCC) signaling was inhibited by intrathecal injection of DCC-siRNA. Results: In BCP rats, the presence of calcitonin gene-related peptide (CGRP)-positive nerve fibers increased in the metastatic bone lesions. The metastatic site showed enrichment of well-differentiated osteoclasts and expressions of netrin-1 and its attractive receptor DCC. Upregulation of DCC and increased phosphorylation levels of focal adhesion kinase (FAK) and Rac family small GTPase 1/Cell division cycle 42 (Rac1/Cdc42) were found in the DRG. Intrathecal administration of DCC-siRNA led to a significant reduction in FAK and Rac1/Cdc42 phosphorylation levels in the DRG, decreased nociceptive nerve innervation, and improved pain behaviors. Conclusions: Netrin-1 may contribute to the activation of the BCP by inducing nociceptive nerve innervation and improving pain behaviors. |
| first_indexed | 2024-04-24T17:38:54Z |
| format | Article |
| id | doaj.art-c88d2f7af32246dfa24616fe7fb6eea4 |
| institution | Directory Open Access Journal |
| issn | 0219-6352 |
| language | English |
| last_indexed | 2024-04-24T17:38:54Z |
| publishDate | 2024-02-01 |
| publisher | IMR Press |
| record_format | Article |
| series | Journal of Integrative Neuroscience |
| spelling | doaj.art-c88d2f7af32246dfa24616fe7fb6eea42024-03-28T02:03:25ZengIMR PressJournal of Integrative Neuroscience0219-63522024-02-012334710.31083/j.jin2303047S0219-6352(23)00639-3Netrin-1 Role in Nociceptive Neuron Sprouting through Activation of DCC Signaling in a Rat Model of Bone Cancer PainZhihao Gong0Yuxin Zhang1Wei Wang2Xin Li3Kai Wang4Xingji You5Jingxiang Wu6Department of Anesthesiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, School of Medicine, 200030 Shanghai, ChinaDepartment of Anesthesiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, School of Medicine, 200030 Shanghai, ChinaDepartment of Anesthesiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, School of Medicine, 200030 Shanghai, ChinaDepartment of Anesthesiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, School of Medicine, 200030 Shanghai, ChinaCentral Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, School of Medicine, 200030 Shanghai, ChinaSchool of Medicine, Shanghai University, 200444 Shanghai, ChinaDepartment of Anesthesiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, School of Medicine, 200030 Shanghai, ChinaBackground: Bone cancer pain (BCP) is a common primary or metastatic bone cancer complication. Netrin-1 plays an essential role in neurite elongation and pain sensitization. This study aimed to determine the role of netrin-1 from the metastatic bone microenvironment in BCP development and identify the associated signaling pathway for the strategy of BCP management. Methods: The rat BCP model was established by intratibial implantation of Walker 256 cells. Von Frey filaments measured the mechanical pain threshold. Movement-induced pain was assessed using limb use scores. Expressions of associated molecules in the affected tibias or dorsal root ganglia (DRG) were measured by immunofluorescence, immunohistochemistry, real-time quantitative polymerase chain reaction, or western blotting. Transduction of deleted in colorectal cancer (DCC) signaling was inhibited by intrathecal injection of DCC-siRNA. Results: In BCP rats, the presence of calcitonin gene-related peptide (CGRP)-positive nerve fibers increased in the metastatic bone lesions. The metastatic site showed enrichment of well-differentiated osteoclasts and expressions of netrin-1 and its attractive receptor DCC. Upregulation of DCC and increased phosphorylation levels of focal adhesion kinase (FAK) and Rac family small GTPase 1/Cell division cycle 42 (Rac1/Cdc42) were found in the DRG. Intrathecal administration of DCC-siRNA led to a significant reduction in FAK and Rac1/Cdc42 phosphorylation levels in the DRG, decreased nociceptive nerve innervation, and improved pain behaviors. Conclusions: Netrin-1 may contribute to the activation of the BCP by inducing nociceptive nerve innervation and improving pain behaviors.https://www.imrpress.com/journal/JIN/23/3/10.31083/j.jin2303047bone cancer painnetrin-1dccfakrac1/cdc42cgrpaxonal guidanceneurite elongationnociception |
| spellingShingle | Zhihao Gong Yuxin Zhang Wei Wang Xin Li Kai Wang Xingji You Jingxiang Wu Netrin-1 Role in Nociceptive Neuron Sprouting through Activation of DCC Signaling in a Rat Model of Bone Cancer Pain Journal of Integrative Neuroscience bone cancer pain netrin-1 dcc fak rac1/cdc42 cgrp axonal guidance neurite elongation nociception |
| title | Netrin-1 Role in Nociceptive Neuron Sprouting through Activation of DCC Signaling in a Rat Model of Bone Cancer Pain |
| title_full | Netrin-1 Role in Nociceptive Neuron Sprouting through Activation of DCC Signaling in a Rat Model of Bone Cancer Pain |
| title_fullStr | Netrin-1 Role in Nociceptive Neuron Sprouting through Activation of DCC Signaling in a Rat Model of Bone Cancer Pain |
| title_full_unstemmed | Netrin-1 Role in Nociceptive Neuron Sprouting through Activation of DCC Signaling in a Rat Model of Bone Cancer Pain |
| title_short | Netrin-1 Role in Nociceptive Neuron Sprouting through Activation of DCC Signaling in a Rat Model of Bone Cancer Pain |
| title_sort | netrin 1 role in nociceptive neuron sprouting through activation of dcc signaling in a rat model of bone cancer pain |
| topic | bone cancer pain netrin-1 dcc fak rac1/cdc42 cgrp axonal guidance neurite elongation nociception |
| url | https://www.imrpress.com/journal/JIN/23/3/10.31083/j.jin2303047 |
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