PAR2-mediated upregulation of BDNF contributes to central sensitization in bone cancer pain.
PAR2-mediated upregulation of BDNF contributes to central sensitization in bone cancer pain.
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PAR2介导的BDNF上调有助于骨癌疼痛的中枢敏化
DOI：
10.1186/1744-8069-10-28
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发表时间：
2014-05-05
期刊：
影响因子：
3.3
通讯作者：
Hua B
中科院分区：
文献类型：
--
作者：
Bao Y;Hou W;Liu R;Gao Y;Kong X;Yang L;Shi Z;Li W;Zheng H;Jiang S;Li C;Qin Y;Hua B
骨癌性疼痛是目前癌症患者治疗的主要临床挑战，脊柱致敏的细胞和分子机制尚不清楚。虽然一些研究证明了蛋白酶激活受体（PAR2）在几种类型的炎症性或神经性疼痛的发病机制中的关键作用，但在骨癌疼痛的啮齿动物模型中，脊髓PAR2及其相关信号在中枢致敏中的作用尚未确定。发现肿瘤细胞植入胫骨可引起明显的热痛觉过敏和机械异常性疼痛，并增强同侧背角的谷氨酸能强度。脑源性神经营养因子（BDNF）在骨癌痛大鼠背角的表达显著增加，阻断脊髓BDNF信号可减弱骨癌痛大鼠的谷氨酸能强度增强、热痛觉过敏和机械异常性痛。脊髓PAR2的表达也显著增加，PAR2信号的抑制改善了BDNF的高涨，增强了谷氨酸能强度，以及热痛觉过敏和机械异常性痛。抑制PAR2信号下游NF-κB通路，也显著降低脊髓BDNF表达、脊髓背角神经元谷氨酸能强度、热痛觉过敏和机械异常性痛。结论PAR2激活可触发NF-κB信号通路，显著上调BDNF功能，对骨癌大鼠脊髓背角谷氨酸能传递增强及热机械超敏反应有重要作用。这提示PAR2 - NF-κ b信号可能成为骨癌患者疼痛治疗的新靶点。
BackgroundBone cancer pain is currently a major clinical challenge for the management of cancer patients, and the cellular and molecular mechanisms underlying the spinal sensitization remain unclear. While several studies demonstrated the critical role of proteinase-activated receptor (PAR2) in the pathogenesis of several types of inflammatory or neuropathic pain, the involvement of spinal PAR2 and the pertinent signaling in the central sensitization is not determined yet in the rodent model of bone cancer pain.FindingsImplantation of tumor cells into the tibias induced significant thermal hyperalgesia and mechanical allodynia, and enhanced glutamatergic strength in the ipsilateral dorsal horn. Significantly increased brain-derived neurotrophic factor (BDNF) expression was detected in the dorsal horn, and blockade of spinal BDNF signaling attenuated the enhancement of glutamatergic strength, thermal hyperalgesia and mechanical allodynia in the rats with bone cancer pain. Significantly increased spinal PAR2 expression was also observed, and inhibition of PAR2 signaling ameliorated BDNF upsurge, enhanced glutamatergic strength, and thermal hyperalgesia and mechanical allodynia. Inhibition of NF-κB pathway, the downstream of PAR2 signaling, also significantly decreased the spinal BDNF expression, glutamatergic strength of dorsal horn neurons, and thermal hyperalgesia and mechanical allodynia.ConclusionThe present study demonstrated that activation of PAR2 triggered NF-κB signaling and significantly upregulated the BDNF function, which critically contributed to the enhancement of glutamatergic transmission in spinal dorsal horn and thermal and mechanical hypersensitivity in the rats with bone cancer. This indicated that PAR2 – NF-κB signaling might become a novel target for the treatment of pain in patients with bone cancer.
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