Activation of spinal chemokine receptor CXCR3 mediates bone cancer pain through an Akt-ERK crosstalk pathway in rats

Previously, we showed that activation of the spinal CXCL9, 10/CXCR3 pathway mediated bone cancer pain (BCP) in rats. However, the cellular mechanism involved is poorly understood. Here, we found that the activated CXCR3 was co-localized with either neurons, microglia, and astrocytes in the spinal cord, or non-peptidergic-, peptidergic-, and A-type neurons in the dorsal root ganglion. The inoculation of Walker-256 mammary gland carcinoma cells into the rat's tibia induced a time-dependent phosphorylation of Akt and extracellular signal-regulated kinase (ERK1/2) in the spinal cord, and CXCR3 was necessary for the phosphorylation of Akt and ERK 1/2. Meanwhile, CXCR3 was co-localized with either pAkt or pERK1/2. Blockage of either Akt or ERK1/2 prevented or reversed the mechanical allodynia in BCP rats. Furthermore, there was cross-activation between PI3K/Akt and Raf/MEK/ERK pathway under the BCP condition. Our results demonstrated that the activation of spinal chemokine receptor CXCR3 mediated BCP through Akt and ERK 1/2 kinase, and also indicated a crosstalk between PI3K/Alct and Raf/MEK/ERK signaling pathways under the BCP condition. Crown Copyright (C) 2014 Published by Elsevier Inc. All rights reserved.

先前，我们发现脊髓中CXCL9、10/CXCR3通路的激活介导了大鼠的骨癌痛（BCP）。然而，所涉及的细胞机制却知之甚少。在此，我们发现活化的CXCR3在脊髓中与神经元、小胶质细胞和星形胶质细胞共定位，在背根神经节中与非肽能、肽能和A型神经元共定位。将Walker - 256乳腺癌细胞接种到大鼠胫骨中，可诱导脊髓中Akt和细胞外信号调节激酶（ERK1/2）发生时间依赖性磷酸化，并且CXCR3对Akt和ERK1/2的磷酸化是必需的。同时，CXCR3与pAkt或pERK1/2共定位。阻断Akt或ERK1/2可预防或逆转BCP大鼠的机械性异常性疼痛。此外，在BCP条件下，PI3K/Akt和Raf/MEK/ERK通路之间存在交叉激活。我们的研究结果表明，脊髓趋化因子受体CXCR3的激活通过Akt和ERK1/2激酶介导BCP，并且还表明在BCP条件下PI3K/Akt和Raf/MEK/ERK信号通路之间存在串扰。版权归皇家所有（C）2014，由爱思唯尔公司出版。保留所有权利。