Department of Pain management, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Department of Anesthesiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Neuroscience. 2019 May 15;406:62-72. doi: 10.1016/j.neuroscience.2019.02.025. Epub 2019 Mar 1.
Chemokines are important regulators of immune, inflammatory, and neuronal responses in peripheral and central pain pathway. The aim of this study was to investigate whether chemokine (C-X-C motif) ligand 13 (CXCL13) and its receptor (C-X-C chemokine receptor type 5, CXCR5) involve in the development of bone cancer pain (BCP) and the regulation of morphine analgesia in rats. The change of pain behaviors in BCP rats were measured by testing paw withdrawal threshold (PWT). The levels of CXCL13, CXCR5 and signal pathway proteins (p-p38, p-ERK and p-AKT etc.) in the spinal cord were measured via western blots. The expression of CXCL13 and CXCR5 in spinal cord was increased in BCP rats. The BCP rats showed decrease of PWTs, which was relieved by CXCR5i. Intrathecally injection of murine recombinant CXCL13 (mrCXCL13) decreased the PWTs of BCP rats and opposed morphine-induced analgesia in BCP rats. In BCP rats, the signal pathway proteins (p38, ERK and AKT) in the spinal cord were activated. CXCL13 and morphine had contrary effect on the phosphorylation of these proteins. MrCXCL13 directly increased the levels of p-p38, p-ERK and p-AKT in BCP rats. However, morphine decreased the levels of these proteins in BCP rats. While blocking the activation of p-p38, p-ERK and p-AKT, morphine analgesia was enhanced. These results suggest CXCL13 participated in bone cancer pain and opposed morphine analgesia via p38, ERK and AKT pathways. It may be a target to enhance pain management in cancer pain patients.
趋化因子是外周和中枢疼痛通路中免疫、炎症和神经元反应的重要调节剂。本研究旨在探讨趋化因子（C-X-C 基序）配体 13（CXCL13）及其受体（C-X-C 趋化因子受体 5，CXCR5）是否参与骨癌痛（BCP）的发展以及对大鼠吗啡镇痛的调节。通过检测足底退缩阈值（PWT）来测量 BCP 大鼠的疼痛行为变化。通过 Western blot 法测量脊髓中 CXCL13、CXCR5 和信号通路蛋白（p-p38、p-ERK 和 p-AKT 等）的水平。BCP 大鼠脊髓中 CXCL13 和 CXCR5 的表达增加。BCP 大鼠的 PWT 降低，CXCR5i 可缓解。鞘内注射鼠重组 CXCL13（mrCXCL13）可降低 BCP 大鼠的 PWT 并拮抗 BCP 大鼠的吗啡诱导镇痛。在 BCP 大鼠中，脊髓中的信号通路蛋白（p38、ERK 和 AKT）被激活。CXCL13 和吗啡对这些蛋白的磷酸化有相反的作用。MrCXCL13 直接增加 BCP 大鼠中 p-p38、p-ERK 和 p-AKT 的水平。然而，吗啡降低了 BCP 大鼠中这些蛋白的水平。阻断 p-p38、p-ERK 和 p-AKT 的激活可增强吗啡镇痛作用。这些结果表明，CXCL13 通过 p38、ERK 和 AKT 途径参与骨癌痛并拮抗吗啡镇痛。它可能是增强癌症疼痛患者疼痛管理的一个靶点。
