糖尿病性疼痛与外周神经脱髓鞘病变

Diabetic neuropathic pain and peripheral nerve demyelination

摘要:

摘 要 目的：研究糖尿病所致外周神经病变特征，比较痛性和非痛性糖尿病的神经病变差异，为进一步探究糖尿病疼痛发生发展机制和治疗提供理论依据。方法：本实验用C57BL/6小鼠和SD大鼠。动物随机分为对照组（腹腔注射柠檬酸钠缓冲溶液）和糖尿病实验组（腹腔注射链脲佐菌素，STZ）。造模前后不同时间点检测其疼痛阈值。根据动物痛阈的不同变化，再将造模成功的糖尿病组动物分为两组：糖尿病疼痛组(STZ-pain) 和糖尿病非疼痛组 (STZ-nonpain)。并于造模后42天将动物麻醉取坐骨神经，用于电镜分析和免疫荧光检测。结果：（1）注射STZ的小鼠 （n=59），78%（46/59）出现持续高血糖（> 13.8 mM）。高血糖组中56%（33/59）的痛阈显著降低；22%（13/59）痛阈不变。 注射STZ的大鼠（n=80），95%（76/80）出现持续高血糖 (>16.6 mM)。高血糖组43.8%（35/80）痛阈显著下降，51.3%（41/80）痛阈不变。血糖正常的大鼠（4/80，5%）和小鼠（13/59，22%）的痛阈不变。（2）电镜观察显示：高血糖疼痛组小鼠的坐骨神经有髓神经的髓鞘厚度减小，轴突/纤维直径比值 (g-ratio) 升高。同时髓鞘相关的基因 (Mpz, Mag) 的mRNA表达降低，神经纤维周围的髓磷脂碱性蛋白 (myelin basic protein, MBP) 亦显著减少。而高血糖非疼痛组与正常对照小鼠的这些外周神经指标无显著差异。结论：在糖尿病神经疼痛中，外周神经脱髓鞘程度与痛过敏密切相关，外周神经脱髓鞘病变是糖尿病性疼痛发生发展的关键因素。 关键词 动物模型；糖尿病性神经病变；疼痛；非疼痛；外周神经；脱髓鞘

Abstract:

Abstract Objective: To provide more reliable and stable parameters for studying the pathogenesis of diabetic neuropathic pain and treatment evaluation, we identified the characteristics of diabetic neuropathy in the peripheral nerves and compared their differences in diabetic animals with and without pain. Methods: Diabetes mellitus was induced in rats and mice, respectively, by intraperitoneal injection of streptozotocin (STZ). Animals were divided into groups of control (intraperitoneal injection of sodium citrate buffer) and diabetes group (intraperitoneal injection of STZ). According to mechanical withdrawal threshold, diabetic rats and mice were further divided into groups of STZ-pain and STZ-nonpain. Six weeks after STZ injection, demyelination of the sciatic nerves and relative protein were detected by Electron Microscope, immunofluorescence. Results: (1) Following i.p. STZ, 78% (46/59) C57BL/6 mice developed high blood glucose (>13.8 mM). Of these hyperglycemic mice, 56% (33/59) developed diabetic neuropathic painful behaviors, the mechanical allodynia, 22% (13/59) did not show changes in mechanical sensitivity. 95% (76/80) SD rats developed high blood glucose (> 16.6 mM). Of which 43.8% (35/80) developed diabetic neuropathic painful behaviors, while the rest 51.3%（41/80）did not exhibit mechanical allodynia. The rats (4/80, 5%) and mice (13/59, 22%) without hyperglycemia did not show changes in mechanical sensitivity. (2) The electric microscope study showed that the g-ratio of sciatic nerve was significantly increased and the thickness of myelin decreased in STZ-pain group compared with that in the groups of STZ-nonpain and the Control. Meanwhile, expression of the genes involving in myelination of nerves, Mpz and Mag as well as the myelin basic protein (MBP) were also decreased in STZ-pain group. Conclusion: The demyelination of periphery nerve plays key roles in the development and maintenance of diabetic neuropathic pain. Key words Animal models; Diabetic neuropathy; Pain; Non-pain; Peripheral nerve; Demyelination.