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

Authors: Hu, Xue-Ming  Zhang, Hui  Xu, Heng  Zhang, Hai-Long  Chen, Li-Ping  Cui, Wen-Qiang  Yang, Wei  Shen, Wen 
Citation: Hu XM, etal., Sci Rep. 2017 Jun 21;7(1):4005. doi: 10.1038/s41598-017-04198-3.
Pubmed: (View Article at PubMed) PMID:28638088
DOI: Full-text: DOI:10.1038/s41598-017-04198-3

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 TCI-induced 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.

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RGD ID: 13838657
Created: 2019-01-08
Species: All species
Last Modified: 2019-01-08
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.