do Prado Filipe C, Vieira Willians F, Fernandes de Magalhães Silviane, Bonet Ivan José Magayewsky, Tambeli Claudia H, Parada Carlos A
Laboratory for Pain Studies, Department of Structural and Functional Biology, Institute of Biology, State University of Campinas (UNICAMP), Campinas, Brazil.
Eur J Neurosci. 2020 Sep;52(6):3642-3651. doi: 10.1111/ejn.14722. Epub 2020 Apr 7.
Diabetic neuropathic hyperalgesia is one of the most common diabetes complications. The physiopathological mechanism of hyperalgesia and the reason by which this condition affects only part of the diabetic patients still unclear. We tested whether an adaptation of primary afferent neurons to hyperglycemia could prevent the development of hyperalgesia. Hyperglycemia was induced in male Wistar rats by a daily administration of a low dose of streptozotocin (STZ), during five consecutive days. Glycemia and mechanical nociceptive thresholds were measured at days 0, 3, 7 and 14 after starting the streptozotocin treatment. In parallel, dorsal root ganglia (DRG) neurons were collected from healthy male Wistar rats and cultured in different glucose concentrations (mimicking slow or fast increase of hyperglycemia), and used for calcium imaging and Western blot analyses. Rats with a slow increase of glycemia did not develop hyperalgesia, while rats with a fast increase of glycemia developed hyperalgesia. DRG neurons suddenly incubated in DMEM containing a high glucose concentration showed a significant increase of calcium influx. However, DRG neurons incubated in DMEM and receiving increasing doses of glucose had the same calcium influx observed in control neurons. The activation of AMPK (α1/α2) was greater in L5-L6 DRG of hyperglycemic and non-hyperalgesic rats, when compared with hyperglycemic and hyperalgesic rats. Our data suggest that the onset speed of hyperglycemia could be related to the development of diabetic neuropathic hyperalgesia, as a maladaptive consequence associated with low activation of AMPK (α1/α2) in peripheral nociceptive neurons when the glycemia suddenly increases.
糖尿病性神经病理性痛觉过敏是最常见的糖尿病并发症之一。痛觉过敏的生理病理机制以及该病症仅影响部分糖尿病患者的原因仍不清楚。我们测试了初级传入神经元对高血糖的适应性是否可以预防痛觉过敏的发生。通过连续五天每日给予低剂量链脲佐菌素（STZ）诱导雄性Wistar大鼠发生高血糖。在开始链脲佐菌素治疗后的第0、3、7和14天测量血糖和机械伤害性感受阈值。同时，从健康雄性Wistar大鼠收集背根神经节（DRG）神经元，并在不同葡萄糖浓度（模拟高血糖的缓慢或快速升高）下培养，用于钙成像和蛋白质免疫印迹分析。血糖缓慢升高的大鼠未发生痛觉过敏，而血糖快速升高的大鼠发生了痛觉过敏。突然在含有高葡萄糖浓度的DMEM中孵育的DRG神经元显示钙内流显著增加。然而，在DMEM中孵育并接受递增剂量葡萄糖的DRG神经元与对照神经元观察到相同的钙内流。与高血糖和痛觉过敏大鼠相比，高血糖和无痛觉过敏大鼠的L5-L6 DRG中AMPK（α1/α2）的激活更大。我们的数据表明，高血糖的起始速度可能与糖尿病性神经病理性痛觉过敏的发生有关，这是血糖突然升高时外周伤害性神经元中AMPK（α1/α2）低激活相关的适应不良后果。
