Chemokine receptor CXCR4 regulates CaMKII/CREB pathway in spinal neurons that underlies cancer-induced bone pain

被引:36
作者
Hu, Xue-Ming [1 ,2 ,3 ]
Zhang, Hui [2 ,3 ]
Xu, Heng [1 ,2 ,3 ]
Zhang, Hai-Long [2 ,3 ]
Chen, Li-Ping [1 ,2 ,3 ]
Cui, Wen-Qiang [4 ]
Yang, Wei [4 ]
Shen, Wen [1 ,2 ,3 ]
机构
[1] Xuzhou Med Univ, Dept Pain Med, Affiliated Hosp, Xuzhou 221002, Jiangsu, Peoples R China
[2] Xuzhou Med Univ, Jiangsu Prov Key Lab Anesthesiol, Xuzhou 221002, Jiangsu, Peoples R China
[3] Xuzhou Med Univ, Jiangsu Prov Key Lab Anesthesia & Analgesia Appli, Xuzhou 221002, Jiangsu, Peoples R China
[4] Fudan Univ, Acad Integrat Med, Sch Basic Med Sci, Dept Integrat Med & Neurobiol, Shanghai 200032, Peoples R China
基金
中国国家自然科学基金;
关键词
NEUROPATHIC PAIN; UP-REGULATION; SIGNALING CONTRIBUTES; ASTROCYTES CONTRIBUTES; CORD ASTROCYTES; RAT MODEL; ACTIVATION; CXCL12; CREB; MAINTENANCE;
D O I
10.1038/s41598-017-04198-3
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
We previously demonstrated that the chemokine receptor CXCR4 plays an important role in cancer-induced bone pain by activating spinal neurons and glial cells. However, the specific neuronal mechanism of CXCR4 signaling is not clear. We further report that CXCR4 contributes to the activation of the neuronal CaMKII/CREB pathway in cancer-induced bone pain. We used a tumor cell implantation (TCI) model and observed that CXCR4, p-CaMKII and p-CREB were persistently up-regulated in spinal neurons. CXCR4 also co-expressed with p-CaMKII and p-CREB, and mediated p-CaMKII and p-CREB expression after TCI. Intrathecal delivery of CXCR4 siRNA or CaMKII inhibitor AIP2 abrogated TC-Iinduced pain hypersensitivity and TCI-induced increase in p-CaMKII and p-CREB expression. Intrathecal injection of the principal ligand for CXCR4, SDF-1, promoted p-CaMKII and p-CREB expression in naive rats, which was prevented by post-administration of CXCR4 inhibitor Plerixafor or PLC inhibitor U73122. Plerixafor, U73122, or AIP2 also alleviated SDF-1-elicited pain behaviors. Intrathecal injection of CXCR4 siRNA significantly suppressed TCI-induced up-regulation of NMDAR1 mRNA and protein, which is a known gene target of CREB. Collectively, these results suggest that the CaMKII/CREB pathway in spinal neurons mediates CXCR4-facilitated pain hypersensitivity in cancer rats.
引用
收藏
页数:12
相关论文
共 50 条
[41]   Tyrosine kinase receptor RON activates MAPK/RSK/CREB signal pathway to enhance CXCR4 expression and promote cell migration and invasion in bladder cancer [J].
Chen, Junfeng ;
Wang, Kejie ;
Ye, Shazhou ;
Meng, Xiangyu ;
Jia, Xiaolong ;
Huang, Youju ;
Ma, Qi .
AGING-US, 2022, 14 (17) :7093-7108
[42]   Inhibition of p38-MAPK signaling pathway attenuates breast cancer induced bone pain and disease progression in a murine model of cancer-induced bone pain [J].
Sukhtankar, Devki ;
Okun, Alec ;
Chandramouli, Anupama ;
Nelson, Mark A. ;
Vanderah, Todd W. ;
Cress, Anne E. ;
Porreca, Frank ;
King, Tamara .
MOLECULAR PAIN, 2011, 7
[43]   The chemokine receptor CXCR4 regulates satellite cell activation, early expansion, and self-renewal, in response to skeletal muscle injury [J].
Shams, Ahmed S. ;
Arpke, Robert W. ;
Gearhart, Micah D. ;
Weiblen, Johannes ;
Mai, Ben ;
Oyler, David ;
Bosnakovski, Darko ;
Mahmoud, Omayma M. ;
Hassan, Gamal M. ;
Kyba, Michael .
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, 2022, 10
[44]   Astrocyte activation in the periaqueductal gray promotes descending facilitation to cancer-induced bone pain through the JNK MAPK signaling pathway [J].
Ni, Hua-dong ;
Xu, Long Sheng ;
Wang, Yungong ;
Li, Hongbo ;
An, Kang ;
Liu, Mingjuan ;
Liu, Qianying ;
Deng, Houshen ;
He, Qiuli ;
Huang, Bing ;
Fang, Jianqiao ;
Yao, Ming .
MOLECULAR PAIN, 2019, 15
[45]   Differences in electrophysiological properties of functionally identified nociceptive sensory neurons in an animal model of cancer-induced bone pain [J].
Zhu, Yong Fang ;
Ungard, Robert ;
Seidlitz, Eric ;
Zacal, Natalie ;
Huizinga, Jan ;
Henry, James L. ;
Singh, Gurmit .
MOLECULAR PAIN, 2016, 12
[46]   Role of extracellular calcitonin gene-related peptide in spinal cord mechanisms of cancer-induced bone pain [J].
Hansen, Rikke R. ;
Vacca, Valentina ;
Pitcher, Thomas ;
Clark, Anna K. ;
Malcangio, Marzia .
PAIN, 2016, 157 (03) :666-676
[47]   Effects of miR-338 on morphine tolerance by targeting CXCR4 in a rat model of bone cancer pain [J].
Mei, Hong-Xia ;
Zhou, Min-Hong ;
Zhang, Xing-Wang ;
Huang, Xi-Xi ;
Wang, Yong-Le ;
Wang, Pei-Fang ;
Zhan, Gong-Hao .
BIOSCIENCE REPORTS, 2017, 37
[48]   The Chemokine Receptor CXCR4 and c-MET Cooperatively Promote Epithelial-Mesenchymal Transition in Gastric Cancer Cells [J].
Cheng, Yu ;
Song, Yongxi ;
Qu, Jinglei ;
Che, Xiaofang ;
Song, Na ;
Fan, Yibo ;
Wen, Ti ;
Xu, Ling ;
Gong, Jing ;
Wang, Xiaoxun ;
Zhang, Chenlu ;
Qu, Xiujuan ;
Liu, Yunpeng .
TRANSLATIONAL ONCOLOGY, 2018, 11 (02) :487-497
[49]   Impacts of anti-nerve growth factor antibody on pain-related behaviors and expressions of opioid receptor in spinal dorsal horn and dorsal root ganglia of rats with cancer-induced bone pain [J].
Yao, Peng ;
Ding, Yuanyuan ;
Wang, Zhibin ;
Ma, Jiaming ;
Hong, Tao ;
Zhu, Yongqiang ;
Li, Hongxi ;
Pan, Shinong .
MOLECULAR PAIN, 2016, 12
[50]   Spinal Cord NMDA Receptor-Mediated Activation of Mammalian Target of Rapamycin Is Required for the Development and Maintenance of Bone Cancer-Induced Pain Hypersensitivities in Rats [J].
Shih, Ming-Hung ;
Kao, Sheng-Chin ;
Wang, Wei ;
Yaster, Myron ;
Tao, Yuan-Xiang .
JOURNAL OF PAIN, 2012, 13 (04) :338-349