The onset speed of hyperglycemia is important to the development of neuropathic hyperalgesia in streptozotocin-induced diabetic rats.

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.