title: 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.
abstract: 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.
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Taiwan; Department of Anesthesiology, Kaohsiung Medical University Hospital, Taiwan.
authors.forename: K-I
authors.initials: KI
authors.lastname: Cheng
authors.forename: H-C
authors.initials: HC
authors.lastname: Wang
authors.forename: Y-T
authors.initials: YT
authors.lastname: Chuang
authors.forename: C-W
authors.initials: CW
authors.lastname: Chou
authors.forename: H-P
authors.initials: HP
authors.lastname: Tu
authors.forename: Y-C
authors.initials: YC
authors.lastname: Yu
authors.forename: L-L
authors.initials: LL
authors.lastname: Chang
authors.forename: C-S
authors.initials: CS
authors.lastname: Lai
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003929:Diabetic Neuropathies / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006930:Hyperalgesia / Q000378:metabolism*; D008297:Male; D017628:Microglia / Q000378:metabolism*; D062552:NAV1.3 Voltage-Gated Sodium Channel / Q000378:metabolism*; D009437:Neuralgia / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D062552:NAV1.3 Voltage-Gated Sodium Channel; C478638:Scn3a protein, rat; D048051:p38 Mitogen-Activated Protein Kinases