Persistent mechanical allodynia positively correlates with an increase in activated microglia and increased P-p38 mitogen-activated protein kinase activation in streptozotocin-induced diabetic rats

Eur J Pain. 2014 Feb;18(2):162-73. doi: 10.1002/j.1532-2149.2013.00356.x. Epub 2013 Jul 19.


Background: In experimental early painful diabetic neuropathy, persistent hyperglycaemia induces dys-regulated sodium channel (Navs) expression in the dorsal root ganglion (DRG) and activates microglia in the spinal dorsal horn (SDH). However, information on diabetes-induced chronic neuropathic pain is limited. Therefore, we investigated abnormal Navs in the DRG and activated glial cells in the SDH of diabetic rats with chronic neuropathic pain.

Methods: Sixty-six rats were divided into diabetic and control groups: control rats (n = 18; 1 mL of normal saline via the right femoral vein) and diabetic rats [n = 48; 60 mg/kg streptozotocin (STZ) via the right femoral vein]. Hindpaw behavioural tests, Navs expression in the DRG, activation of glial cells in the SDH and the number of neurons in the SDH were measured at 1 and 2 weeks, and 1, 2, 3 and 6 months following saline and STZ administration.

Results: All diabetic rats exhibited hyperglycaemia from day 7 to 6 months. The diabetic rats decreased withdrawal threshold to mechanical stimuli but had blunted responses to thermal stimuli. Consistent up-regulation of Nav1.3 and down-regulation of Nav1.8 was observed. Microglial cells were activated early in the SDH and lasted for 6 months. A positive correlation between mechanical allodynia, Nav1.3 and microglial activation was observed. In addition, microglia activation in the SDH of STZ-induced diabetes was mediated, in part, by phosphorylation of p-38 mitogen-activated protein kinase.

Conclusions: Diabetic rats showed hindpaw mechanical allodynia for 6 months. Persistent mechanical allodynia was positively associated with sustained increased activation of Nav1.3 and increased p38 phosphorylation in activated microglia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetic Neuropathies / metabolism
  • Disease Models, Animal
  • Enzyme Activation
  • Hyperalgesia / metabolism*
  • Male
  • Microglia / metabolism*
  • NAV1.3 Voltage-Gated Sodium Channel / metabolism*
  • Neuralgia / metabolism*
  • Phosphorylation
  • Rats
  • Rats, Sprague-Dawley
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • NAV1.3 Voltage-Gated Sodium Channel
  • Scn3a protein, rat
  • p38 Mitogen-Activated Protein Kinases