a-硫辛酸对于电压门控性钠通道介导的糖尿病大鼠肠道痛觉过敏的影响
Sensitization of sodium channels contributes to colonic visceral hypersensitivity in STZ induced diabetic rats and the antinociceptive effects of α-lipoic acid
背景：通过前期我们实验发现脊髓背根节神经元上电压门控性钠离子通道NaV1.7和NaV1.8参与形成糖尿病大鼠肠道痛觉过敏。目的：探讨α-硫辛酸对电压门控性钠离子通道的表达和功能调控及其对肠道痛觉过敏的影响。方法：1. 建立糖尿病大鼠模型：实验动物选用160-180g的雌性SD大鼠，给予链脲佐菌素(STZ，65mg/kg)腹腔注射诱导糖尿病模型。两周后空腹血糖（FBG）超过15mmol/L为造模成功。给予3周病程的糖尿病大鼠腹腔注射α-硫辛酸连续一周，为ALA组。NS组给予3周病程的糖尿病大鼠腹腔注射相同体积的生理盐水。2. 直结肠扩张试验： 给予糖尿病大鼠腹腔注射30mg/kg，60mg/kg，120mg/kg三个不同剂量组α-硫辛酸，观察注射α-硫辛酸干预后大鼠痛阈的变化。3.全细胞膜片钳技术：用荧光染料DiI直结肠注射，逆行标记直结肠投射的特异性脊髓背根神经节神经元，应用全细胞膜片钳技术记录α-硫辛酸处理组及对应生理盐水组直结肠特异性DRG（T13-L2 DRGs）神经元的兴奋性和电压门控性钠通道电流的变化特性。4.蛋白质免疫印迹（Western Blotting）：检测两组大鼠T13-L2 DRGs中NaV1.7和NaV1.8蛋白表达水平。结果：给予不同剂量的抗氧化剂α-硫辛酸连续腹腔注射一周后（30,60,120mg/kg），可翻转糖尿病大鼠的肠道痛觉过敏。以60mg/kg剂量为例，α-硫辛酸干预后可显著下调糖尿病大鼠直结肠特异性DRG神经元NaV1.7、NaV1.8的表达，降低钠电流的密度，降低DRG神经元的兴奋性(P <0.05，P<0.01)。结论：抗氧化剂α-硫辛酸可使糖尿病大鼠直结肠特异性DRG神经元中NaV1.7和NaV1.8表达下调，钠通道电流密度降低，神经元的兴奋性减小，提示氧化应激机制参与调控直结肠特异性DRG神经元电压门控性钠离子通道NaV1.7和NaV1.8的表达及功能。
Background: Intestinal dysfunction is a common chronic complication of diabetes mellitus, the underlying mechanisms of colonic visceral hypersensitivity in diabetic patients remain elusive. Recently, several lines of evidence suggest that the change of ion channels in dorsal root ganglion (DRG) neurons play a significant role in diabetic neuropathic pain.Our previous study investigated the changes in function and expression of voltage-gated sodium channels (VGSCs) of DRG neurons in visceral hypersensitivity of STZ-induced diabetic rats. In this study, we aim to explore the effect of α-lipoic acid on VGSCs activities and visceral hypersensitivity of diabetic rats. Methods: Diabetic model was induced by a single intraperitoneal injection of streptozotocin (STZ; 65mg/kg) in adult female rats. Behavioral response to colorectal distention (CRD) was used to examine visceral hypersensitivity . Colon-specific DRG neurons were labeled with DiI and acutely dissociated for measuring excitability and sodium channel current under whole-cell patch clamp configurations. Western blot analysis was employed to measure the expression of NaV1.7 and NaV1.8 in colon-specific DRGs.Results:, Intraperitoneal injection with α-lipoic acid for 1 week, remarkably reduced the expression of NaV1.7 and NaV1.8 in STZ-induced diabetic rats. Furthermore, it also suppressed neuronal excitability, sodium channel current density, and attenuated visceral hypersensitivity in diabetic rats as well. Conclusion: Our findings suggest that α-lipoic acid attenuates diabetic visceral hypersensitivity by suppressing the expression of NaV1.7 and NaV1.8.
胡吉、徐广银、宋珍源、张弘弘
基础医学神经病学、精神病学生理学
-硫辛酸糖尿病内脏痛脊髓背根神经节电压门控性钠通道
α-lipoic aciddiabetesvisceral hypersensitivitydorsal root ganglionvoltage-gated sodium channels
胡吉,徐广银,宋珍源,张弘弘.a-硫辛酸对于电压门控性钠通道介导的糖尿病大鼠肠道痛觉过敏的影响[EB/OL].(2015-05-28)[2025-08-10].http://www.paper.edu.cn/releasepaper/content/201505-411.点此复制
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