Department of Pain Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China.
Jiangsu Province Key Laboratory of Anesthesiology and Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China.
Sci Rep. 2017 Jun 21;7(1):4005. 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.
我们之前的研究表明，趋化因子受体 CXCR4 通过激活脊髓神经元和神经胶质细胞在癌痛骨转移中发挥重要作用。然而，CXCR4 信号的具体神经元机制尚不清楚。我们进一步报道，CXCR4 有助于癌痛骨转移中神经元 CaMKII/CREB 通路的激活。我们使用肿瘤细胞植入（TCI）模型，观察到 CXCR4、p-CaMKII 和 p-CREB 在脊髓神经元中持续上调。CXCR4 还与 p-CaMKII 和 p-CREB 共表达，并介导 TCI 后的 p-CaMKII 和 p-CREB 表达。鞘内给予 CXCR4 siRNA 或 CaMKII 抑制剂 AIP2 可消除 TCI 诱导的痛觉过敏和 TCI 诱导的 p-CaMKII 和 p-CREB 表达增加。鞘内注射 CXCR4 的主要配体 SDF-1 可促进正常大鼠的 p-CaMKII 和 p-CREB 表达，而 CXCR4 抑制剂 Plerixafor 或 PLC 抑制剂 U73122 可阻止这一作用。Plerixafor、U73122 或 AIP2 也可减轻 SDF-1 引起的疼痛行为。鞘内注射 CXCR4 siRNA 可显著抑制 TCI 诱导的 NMDAR1 mRNA 和蛋白的上调，NMDAR1 是 CREB 的已知基因靶点。综上所述，这些结果表明，脊髓神经元中的 CaMKII/CREB 通路介导了 CXCR4 促进的癌痛大鼠痛觉过敏。
