Inhibition of Connexin 43 and Phosphorylated NR2B in Spinal Astrocytes Attenuates Bone Cancer Pain in Mice.
Inhibition of Connexin 43 and Phosphorylated NR2B in Spinal Astrocytes Attenuates Bone Cancer Pain in Mice.
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抑制脊髓星形胶质细胞中的连接蛋白 43 和磷酸化 NR2B 可减轻小鼠骨癌疼痛
DOI：
10.3389/fncel.2018.00129
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发表时间：
2018
影响因子：
5.3
通讯作者：
Wu L
中科院分区：
文献类型：
--
作者：
Yang H;Yan H;Li X;Liu J;Cao S;Huang B;Huang D;Wu L
骨癌疼痛（BCP）在晚期癌症患者中常见，当肿瘤转移到骨时。对BCP复杂的发病机制认识有限，导致临床治疗效果不佳。以往的研究表明，缝隙连接（GJ）和半通道形成蛋白--星形胶质细胞特异性连接蛋白（Cx）43和N-甲基-D-天冬氨酸受体（NMDARs），尤其是磷酸化NMDAR 2B亚基（NR 2B）磷酸化NR 2B亚基（p-NR 2B）参与BCP的形成。然而，BCP中Cx43和p-NR 2B之间的关系尚不清楚。在本研究中，我们研究了Cx 43，胶质细胞酸性蛋白（GFAP，星形胶质细胞的标志物）和p-NR 2B在BCP小鼠模型中的表达，该模型通过股内接种刘易斯肺癌（LLC）细胞，通过鞘内注射GJ/半通道阻断剂甘珀酸（CARB）和NMDAR拮抗剂MK 801，分别建立。结果发现，小鼠股内接种LLC细胞后，可模拟BCP的特征，从接种后第7天到第21天，BCP小鼠Cx43、GFAP和p-NR 2B的表达明显增加，并呈时间依赖性，自发痛和机械性痛觉超敏反应逐渐加重。此外，Cx43主要在脊髓星形胶质细胞中表达。CARB和MK 801均能抑制BCP小鼠Cx43、GFAP和p-NR 2B的表达，并能减轻BCP小鼠的疼痛敏感性。此外，Cx43与p-NR 2B共定位于SDH中，这进一步证明BCP小鼠的脊髓星形胶质细胞中存在功能性NR 2B。我们的研究结果表明，抑制脊髓星形胶质细胞中的Cx43和p-NR 2B可以减轻小鼠BCP，SDH星形胶质细胞中的Cx43和p-NR 2B可能通过它们的联合作用在小鼠BCP的发生和维持中起重要作用。这些结果可能为预防和/或治疗BCP提供潜在的治疗靶点。
Bone cancer pain (BCP) is common in patients with advanced cancers when the tumors are metastasized to bone. The limited understanding of the complex pathogenesis of BCP leads to the poor effectiveness of clinical treatment. Previous studies have shown that astrocyte-specific connexin (Cx) 43, a forming protein of gap junction (GJ) and hemichannel, and N-methyl-D-aspartate receptors (NMDARs), especially the phosphorylated NMDAR 2B subunit (NR2B) phosphorylated NR2B (p-NR2B) subunit are involved in BCP. However, the relationship between Cx43 and p-NR2B in BCP remains unclear. In the present study, we investigated the expressions of Cx43, glial fibrillary acidic protein (GFAP, a marker of astrocytes), and p-NR2B in the spinal dorsal horn (SDH) in a mouse model of BCP established by intra-femural inoculation of Lewis lung carcinoma (LLC) cells via intrathecal (ith) injection of the GJ/hemichannel blocker carbenoxolone (CARB) and the NMDAR antagonist MK801, respectively. We found that the characters of BCP were mimicked by intra-femural inoculation of LLC cells in mice, and the expressions of Cx43, GFAP and p-NR2B in BCP mice were remarkably increased in a time-dependent manner from day 7 to day 21 after cell inoculation with a gradual aggravate in spontaneous pain and mechanical allodynia. Furthermore, Cx43 was predominantly expressed in the spinal astrocytes. Both CARB and MK801 inhibited the expressions of Cx43, GFAP and p-NR2B with attenuated pain hypersensitivity in BCP mice. In addition, Cx43 was co-localized with p-NR2B in the SDH, which further evidenced the presence of functional NR2B in the spinal astrocytes in BCP mice. Our findings demonstrate that inhibition of Cx43 and p-NR2B in spinal astrocytes could attenuate BCP in mice and Cx43 and p-NR2B in the astrocytes of the SDH may play an important role via their combination action in the development and maintenance of BCP in mice. These results may provide a potential therapeutic target in the prevention and/or treatment of BCP.
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影响因子：
5.4
作者：
Cheng, Xiao;Hou, Zijun;Cai, Yefeng
通讯作者：
Cai, Yefeng
影响因子：
6.2
作者：
Almad AA;Doreswamy A;Gross SK;Richard JP;Huo Y;Haughey N;Maragakis NJ
通讯作者：
Maragakis NJ
影响因子：
3.9
作者：
Azarashvili T;Baburina Y;Grachev D;Krestinina O;Papadopoulos V;Lemasters JJ;Odinokova I;Reiser G
通讯作者：
Reiser G
影响因子：
4.4
作者：
Hang, Li-Hua;Li, Shu-Na;Shao, Dong-Hua
通讯作者：
Shao, Dong-Hua
影响因子：
14.5
作者：
Chen, Gang;Park, Chul-Kyu;Ji, Ru-Rong
通讯作者：
Ji, Ru-Rong