Extracellular signal-regulated protein kinase activation in spinal cord contributes to pain hypersensitivity in a mouse model of type 2 diabetes
Extracellular signal-regulated protein kinase activation in spinal cord contributes to pain hypersensitivity in a mouse model of type 2 diabetes
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脊髓中细胞外信号调节蛋白激酶的激活导致 2 型糖尿病小鼠模型的疼痛过敏
DOI：
10.1007/s12264-013-1387-y
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发表时间：
2013-11
影响因子：
5.6
通讯作者：
Zhang Yu-Qiu
中科院分区：
文献类型：
--
作者：
Xu Xiang;Chen Hui;Ling Bing-Yu;Xu Lan;Cao Hong;Zhang Yu-Qiu
疼痛性周围神经病变是糖尿病的常见并发症。疼痛的症状可能成为降低糖尿病患者生活质量的主要因素，而缺乏有效的治疗。在本研究中，我们旨在研究2型糖尿病动物模型db/db小鼠早期糖尿病疼痛阈值的变化及其分子机制。我们发现(1)db/db小鼠（瘦素受体缺失突变，以肥胖和高血糖为特征）在糖尿病早期表现出对机械和热刺激的超敏反应；(2)与野生型小鼠相比，db/db小鼠脊髓和背根神经节中磷酸化的细胞外信号调节激酶（pERK），而非总ERK显著增加。在表达neun的神经元和表达gapap的星形胶质细胞中，pERK免疫反应性增加，但在表达iba -1的小胶质细胞中没有增加；(3)单次和连续（5天）鞘内注射U0126（每天2 nmol），一种选择性MEK （ERK激酶）抑制剂，从8周龄开始，减轻了von-Frey试验中的双侧机械异常性痛和Hargreave试验中的热痛觉过敏；(4) db/db小鼠在福尔马林试验中也表现出增加的有害行为，而这种行为被鞘内注射U0126阻断。此外，注射福尔马林后，pERK1和pERK2的表达上调。我们的研究结果表明，脊髓神经元和星形胶质细胞ERK的激活与2型糖尿病动物模型的疼痛超敏反应有关。抑制ERK通路可能为2型糖尿病疼痛控制提供一种新的治疗方法。
Painful peripheral neuropathy is a common complication of diabetes mellitus. The symptom of pain can become a major factor that decreases the quality of life of patients with diabetes, while effective treatment is lacking. In the present study, we aimed to investigate the changes of pain threshold in the early stage of diabetes in db/db mice, an animal model of type 2 diabetes mellitus, and the underlying molecular mechanisms. We found that (1) db/db mice (with a leptin receptor-null mutation and characterized by obesity and hyperglycemia) showed hypersensitivity to mechanical and thermal stimuli at the early stage of diabetes; (2) phosphorylated extracellular signalregulated kinase (pERK), but not total ERK in the spinal cord and dorsal root ganglia in db/db mice significantly increased compared with wild-type mice. The increased pERK immunoreactivity occurred in both NeuN-expressing neurons and GFAPexpressing astrocytes, but not in Iba-1-expressing microglia; (3) both single and consecutive (for 5 days) intrathecal injections of U0126 (2 nmol per day), a selective MEK (an ERK kinase) inhibitor beginning at 8 weeks of age, attenuated the bilateral mechanical allodynia in the von-Frey test and heat hyperalgesia in Hargreave’s test; and (4) db/db mice also displayed increased nocifensive behavior during the formalin test, and this was blocked by intrathecal injection of U0126. Also, the expression of pERK1 and pERK2 was upregulated following the formalin injection. Our results suggested that the activation of ERK in spinal neurons and astrocytes is correlated with pain hypersensitivity of the type 2 diabetes animal model. Inhibiting the ERK pathway may provide a new therapy for pain control in type 2 diabetes.
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影响因子：
25
作者：
Ji, RR;Baba, H;Woolf, CJ
通讯作者：
Woolf, CJ
影响因子：
6.2
作者：
Tsuda, Makoto;Ueno, Hikaru;Inoue, Kazuhide
通讯作者：
Inoue, Kazuhide
DOI：
10.1096/fasebj.21.6.a1199-c
发表时间：
2007-04
期刊：
The FASEB Journal
影响因子：
--
作者：
V. Drel;N. Mashtalir;O. Ilnytska;Valeryi V. Lyzogubov;Fei Li;Jeho Shin;I. Obrosova
通讯作者：
V. Drel;N. Mashtalir;O. Ilnytska;Valeryi V. Lyzogubov;Fei Li;Jeho Shin;I. Obrosova
影响因子：
5.9
作者：
O'Connor, Alec B.;Dworkin, Robert H.
通讯作者：
Dworkin, Robert H.
影响因子：
2.9
作者：
Calcutt, NA;Stiller, CO;Malmberg, AB
通讯作者：
Malmberg, AB