Neuroscience Research Institute and Center for Pain Medicine, Peking University, 38 Xueyuan Road, Beijing 100191, China Department of Neurobiology, Parker University Research Institute, 2540 Walnut Hill Lane, Dallas, TX 75229, USA.
Pain. 2013 Dec;154(12):2823-2835. doi: 10.1016/j.pain.2013.08.017. Epub 2013 Aug 22.
Treating bone cancer pain poses a major clinical challenge, and the mechanisms underlying bone cancer pain remain elusive. EphrinB-EphB receptor signaling may contribute to bone cancer pain through N-methyl-d-aspartate receptor neuronal mechanisms. Here, we report that ephrinB-EphB signaling may also act through a Toll-like receptor 4 (TLR4)-glial cell mechanism in the spinal cord. Bone cancer pain was induced by tibia bone cavity tumor cell implantation (TCI) in rats. TCI increased the expression of TLR4 and the EphB1 receptor, the activation of astrocytes and microglial cells, and increased levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). The increased expression of TLR4 and EphB1 were colocalized with each other in astrocytes and microglial cells. Spinal knockdown of TLR4 suppressed TCI-induced behavioral signs of bone cancer pain. The TCI-induced activation of astrocytes and microglial cells, as well as the increased levels of IL-1β and TNF-α, were inhibited by intrathecal administration of TLR4-targeting siRNA2 and the EphB receptor antagonist EphB2-Fc, respectively. The administration of EphB2-Fc suppressed the TCI-induced increase of TLR4 expression but siRNA2 failed to affect TCI-induced EphB1 expression. Intrathecal administration of an exogenous EphB1 receptor activator, ephrinB2-Fc, increased the expression of TLR4 and the levels of IL-1β and TNF-α, activated astrocytes and microglial cells, and induced thermal hypersensitivity. These ephrinB2-Fc-induced alterations were suppressed by spinal knockdown of TLR4. This study suggests that TLR4 may be a potential target for preventing or reversing bone cancer pain and other similar painful processes mediated by ephrinB-EphB receptor signaling.
治疗骨癌疼痛是一个重大的临床挑战，而骨癌疼痛的机制仍难以捉摸。EphrinB-EphB 受体信号可能通过 N-甲基-D-天冬氨酸受体神经元机制促进骨癌疼痛。在这里，我们报告 EphrinB-EphB 信号也可能通过脊髓中的 Toll 样受体 4（TLR4）-神经胶质细胞机制发挥作用。通过胫骨骨腔肿瘤细胞植入（TCI）在大鼠中诱导骨癌疼痛。TCI 增加了 TLR4 和 EphB1 受体的表达，星形胶质细胞和小胶质细胞的激活，以及白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）的水平增加。TLR4 和 EphB1 的表达增加在星形胶质细胞和小胶质细胞中彼此共定位。TLR4 的脊髓敲低抑制了 TCI 诱导的骨癌疼痛行为迹象。TLR4 靶向 siRNA2 和 EphB 受体拮抗剂 EphB2-Fc 分别抑制 TCI 诱导的星形胶质细胞和小胶质细胞的激活以及 IL-1β 和 TNF-α 水平的增加。EphB2-Fc 的给药抑制了 TCI 诱导的 TLR4 表达增加，但 siRNA2 未能影响 TCI 诱导的 EphB1 表达。鞘内给予外源性 EphB1 受体激活剂 EphrinB2-Fc 增加了 TLR4 和 IL-1β 和 TNF-α 水平的表达，激活了星形胶质细胞和小胶质细胞，并诱导了热过敏。这些 EphrinB2-Fc 诱导的改变被脊髓 TLR4 敲低抑制。这项研究表明，TLR4 可能是预防或逆转骨癌疼痛和其他类似由 EphrinB-EphB 受体信号介导的疼痛过程的潜在靶点。
