Bilateral downregulation of Nav1.8 in dorsal root ganglia of rats with bone cancer pain induced by inoculation with Walker 256 breast tumor cells.
Bilateral downregulation of Nav1.8 in dorsal root ganglia of rats with bone cancer pain induced by inoculation with Walker 256 breast tumor cells.
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DOI：
10.1186/1471-2407-10-216
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发表时间：
2010-05-20
期刊：
影响因子：
3.8
通讯作者：
Yu WF
中科院分区：
文献类型：
--
作者：
Miao XR;Gao XF;Wu JX;Lu ZJ;Huang ZX;Li XQ;He C;Yu WF
快速有效地治疗癌症引起的骨痛仍然是临床挑战，骨转移患者更有可能经历剧烈疼痛。电压门控钠通道 Nav1.8 在伤害感受器功能的许多方面发挥着关键作用。因此，我们对癌症疼痛的大鼠模型进行了表征，并研究了 Nav1.8 的潜在作用。成年雌性 Wistar 大鼠用于该研究。通过将 Walker 256 乳腺癌肉瘤细胞接种到胫骨中来诱发癌痛。手术后，评估机械和热痛觉过敏以及行走评分，以确定与疼痛相关的行为。我们使用实时 RT-PCR 测定术后 16-19 天双侧 L4/L5 背根神经节 (DRG) 中 Nav1.8 mRNA 的表达。采用Western blotting和免疫荧光法比较荷瘤大鼠和假手术大鼠L4/L5 DRG中Nav1.8的表达和分布。术后 14-16 天，鞘内注射针对 Nav1.8 的反义寡脱氧核苷酸 (ODN)，以降低 Nav1.8 蛋白的表达，并观察到疼痛相关行为的变化。荷瘤大鼠从接种 Walker 256 细胞后第 7 天开始表现出机械性痛觉过敏和动态诱发的疼痛。在癌痛晚期（术后第 16-19 天），通过实时 RT-PCR 评估，荷瘤大鼠同侧 L4/L5 DRG 的标准化 Nav1.8 mRNA 水平显着低于假手术组。 Western-blot显示荷瘤大鼠双侧DRG中Nav1.8蛋白总表达量显着下降。此外，免疫荧光显示，癌痛大鼠双侧背根神经节中仅小神经元Nav1.8蛋白表达显着下调。给予针对 Nav1.8 的反义 ODN 后，Nav1.8 蛋白表达显着降低，荷瘤大鼠的机械痛觉过敏和动态诱发的疼痛减轻。这些发现表明 Nav1.8 在骨癌疼痛的发生和维持中发挥作用。
Rapid and effective treatment of cancer-induced bone pain remains a clinical challenge and patients with bone metastasis are more likely to experience severe pain. The voltage-gated sodium channel Nav1.8 plays a critical role in many aspects of nociceptor function. Therefore, we characterized a rat model of cancer pain and investigated the potential role of Nav1.8. Adult female Wistar rats were used for the study. Cancer pain was induced by inoculation of Walker 256 breast carcinosarcoma cells into the tibia. After surgery, mechanical and thermal hyperalgesia and ambulation scores were evaluated to identify pain-related behavior. We used real-time RT-PCR to determine Nav1.8 mRNA expression in bilateral L4/L5 dorsal root ganglia (DRG) at 16-19 days after surgery. Western blotting and immunofluorescence were used to compare the expression and distribution of Nav1.8 in L4/L5 DRG between tumor-bearing and sham rats. Antisense oligodeoxynucleotides (ODNs) against Nav1.8 were administered intrathecally at 14-16 days after surgery to knock down Nav1.8 protein expression and changes in pain-related behavior were observed. Tumor-bearing rats exhibited mechanical hyperalgesia and ambulatory-evoked pain from day 7 after inoculation of Walker 256 cells. In the advanced stage of cancer pain (days 16-19 after surgery), normalized Nav1.8 mRNA levels assessed by real-time RT-PCR were significantly lower in ipsilateral L4/L5 DRG of tumor-bearing rats compared with the sham group. Western-blot showed that the total expression of Nav1.8 protein significantly decreased bilaterally in DRG of tumor-bearing rats. Furthermore, as revealed by immunofluorescence, only the expression of Nav1.8 protein in small neurons down regulated significantly in bilateral DRG of cancer pain rats. After administration of antisense ODNs against Nav1.8, Nav1.8 protein expression decreased significantly and tumor-bearing rats showed alleviated mechanical hyperalgesia and ambulatory-evoked pain. These findings suggest that Nav1.8 plays a role in the development and maintenance of bone cancer pain.
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影响因子：
5.5
作者：
Brock, JA;McLachlan, EM;Belmonte, C
通讯作者：
Belmonte, C
影响因子：
4
作者：
Devor, M
通讯作者：
Devor, M
影响因子：
1.7
作者：
Kerr, BJ;Souslova, V;Wood, JN
通讯作者：
Wood, JN
影响因子：
6.1
作者：
Buffon, Andreia;Ribeiro, Vanessa B.;Sarkis, Joao J. F.
通讯作者：
Sarkis, Joao J. F.
DOI：
10.1073/pnas.96.14.7640
发表时间：
1999-07-06
影响因子：
11.1
作者：
Porreca, F;Lai, J;Hunter, JC
通讯作者：
Hunter, JC