Upregulation of calcium channel alpha-2-delta-1 subunit in dorsal horn contributes to spinal cord injury-induced tactile allodynia
Upregulation of calcium channel alpha-2-delta-1 subunit in dorsal horn contributes to spinal cord injury-induced tactile allodynia
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DOI：
10.1016/j.spinee.2018.01.010
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发表时间：
2018-06-01
期刊：
影响因子：
4.5
通讯作者：
Noguchi, Koichi
中科院分区：
文献类型：
--
作者：
Kusuyama, Kazuki;Tachibana, Toshiya;Noguchi, Koichi
背景：脊髓损伤（SCI）通常不仅导致运动瘫痪，还导致神经病理性疼痛（NeuP）的出现。这两种疾病都可能损害SCI患者的生活质量。在临床领域，众所周知，普瑞巴林结合电压门控钙通道α-2-δ-1（α（2）δ-1）亚基，对SCI后的NeuP具有治疗作用。先前的研究已经通过蛋白质印迹分析证明，SCI增加了SCI大鼠L4-L 6背侧脊髓中的α（2）δ-1，并且α（2）δ-1的增加与后爪的触觉异常性疼痛相关。然而，脊髓背角中α（2）δ-1蛋白增加的详细特征和普瑞巴林对SCI诱导的NeuP的作用机制尚未完全研究。目的：本研究旨在研究大鼠胸段SCI后腰段脊髓中α（2）δ-1表达的详细分布以及普瑞巴林对SCI大鼠治疗效果的相关性。雄性Sprague-Dawley大鼠使用IH撞击器装置进行胸（T10）脊髓挫伤。脊髓损伤大鼠在脊髓损伤后给予普瑞巴林（30 mg/kg），每天1次，连续2周，共4周。采用免疫组织化学和原位杂交histochemistry.RESULTS：观察到机械刺激后爪的缩阈显著降低，持续2周，SCI后至少持续4周。在对照组大鼠中，α（2）δ-1免疫反应性的表达主要在腰椎背角的I和II层中检测到。SCI后4周，胸部SCI显着增加了腰背角I和II层中的α（2）delta-1免疫反应性;然而，胸部SCI并不影响L4和L5背根节中α（2）delta-1 mRNA的表达。与此同时，腰髓中alpha（2）delta-1 mRNAs的信号强度从SCI后第7天开始增加，并持续至少28天。细胞分析显示SCI增加了I和II层中表达α 2 δ 1的细胞数量。脊髓损伤大鼠后爪的触觉异常性疼痛在普瑞巴林治疗后被逆转，并维持21天。结论：本研究结果提示，脊髓损伤后L4和LS背角α 2 δ 1的表达增加是由于脊髓腰段神经元α 2 δ 1表达增加所致。这种增加可能与后爪NeuP的发展以及普瑞巴林对SCI后中枢NeuP的治疗作用有关。(C)2018爱思唯尔公司All rights reserved.
BACKGROUND CONTEXT: Spinal cord injury (SCI) commonly results not only in motor paralysis but also in the emergence of neuropathic pain (NeuP). both of which can impair the quality of life for patients with SCI. In the clinical field, it is well known that pregabalin, which binds to the voltage-gated calcium channel alpha-2-delta-1 (alpha(2)delta-1) subunit has therapeutic effects on NeuP after SCI. A previous study has demonstrated that SCI increased alpha(2)delta-1 in the L4-L6 dorsal spinal cord of SCI rats by Western blot analysis and that the increase of alpha(2)delta-1 was correlated with tactile allodynia of the hind paw. However, the detailed feature of an increase in alpha(2)delta-1 protein in the spinal dorsal horn and the mechanism of pregabalin effect on SCI-induced NeuP have not been fully examined.PURPOSE: This study aimed to examine the detailed distribution of alpha(2)delta-1 expression in the lumbar spinal cord after thoracic SCI in rats and the correlation of the therapeutic effect of pregabalin in SCI rats.STUDY DESIGN: Male Sprague-Dawley rats underwent thoracic (T10) spinal cord contusion injury using the IH impactor device. Spinal cord injury rats received pregabalin (30 mg/kg) once a day for 2 weeks over a 4-week period after SCI.METHODS: The mechanical threshold in the rat hind paw was measured over 4 weeks. Alpha-2delta-1 expression in the lumbar spinal cord and in the dorsal root ganglion (DRG) was analyzed using immunohistochemistry and in situ hybridization histochemistry.RESULTS: A significant reduction of the withdrawal threshold of mechanical stimuli to the hind paw was observed for 2 weeks and continued at least 4 weeks after SCI. In the control rats, expression of alpha(2)delta-1 immunoreactivity was detected mainly in laminae I and II in the lumbar dorsal horn. Thoracic SCI significantly increased alpha(2)delta-1 immunoreactivity in laminae I and II in the lumbar dorsal horn 4 weeks after SCI; however, thoracic SCI did not affect the expression of alpha(2)delta-1 mRNA in the L4 and L5 DRGs. Meanwhile, the signal intensity of alpha(2)delta-1 mRNAs in the lumbar spinal cord increased from Day 7 and continued for at least 28 days after SCI. Cellular analysis showed that SCI increased the number of alpha(2)delta-1-expressing cells in laminae I and II. The tactile allodynia of the hind paw in the SCI rats was reversed after pregabalin treatment and was maintained for 21 days. This administration of pregabalin decreased the alpha(2)delta-1 immunoreactivity significantly in the lumbar dorsal horn of thoracic SCI rats at 28 days after SCI.CONCLUSIONS: The present study results suggest that an increase of alpha(2)delta-1 in the L4 and LS dorsal horns after thoracic SCI is derived from the increase in the expression in lumbar spinal neurons. This increase may be involved in the development of NeuP in the hind paws and the therapeutic effect of pregabalin on central NeuP after SCI. (C) 2018 Elsevier Inc. All rights reserved.