title: Pioglitazone Inhibits the Development of Hyperalgesia and Sensitization of Spinal Nociresponsive Neurons in Type 2 Diabetes.
abstract: Thiazolidinedione drugs (TZDs) such as pioglitazone are approved by the U.S. Food and Drug Administration for the treatment of insulin resistance in type 2 diabetes. However, whether TZDs reduce painful diabetic neuropathy (PDN) remains unknown. Therefore, we tested the hypothesis that chronic administration of pioglitazone would reduce PDN in Zucker Diabetic Fatty (ZDF(fa/fa) [ZDF]) rats. Compared with Zucker Lean (ZL(fa/+)) controls, ZDF rats developed: (1) increased blood glucose, hemoglobin A1c, methylglyoxal, and insulin levels; (2) mechanical and thermal hyperalgesia in the hind paw; (3) increased avoidance of noxious mechanical probes in a mechanical conflict avoidance behavioral assay, to our knowledge, the first report of a measure of affective-motivational pain-like behavior in ZDF rats; and (4) exaggerated lumbar dorsal horn immunohistochemical expression of pressure-evoked phosphorylated extracellular signal-regulated kinase. Seven weeks of pioglitazone (30 mg/kg/d in food) reduced blood glucose, hemoglobin A1c, hyperalgesia, and phosphorylated extracellular signal-regulated kinase expression in ZDF. To our knowledge, this is the first report to reveal hyperalgesia and spinal sensitization in the same ZDF animals, both evoked by a noxious mechanical stimulus that reflects pressure pain frequently associated with clinical PDN. Because pioglitazone provides the combined benefit of reducing hyperglycemia, hyperalgesia, and central sensitization, we suggest that TZDs represent an attractive pharmacotherapy in patients with type 2 diabetes-associated pain.
  
  
  CONCLUSIONS
  To our knowledge, this is the first preclinical report to show that: (1) ZDF rats exhibit hyperalgesia and affective-motivational pain concurrent with central sensitization; and (2) pioglitazone reduces hyperalgesia and spinal sensitization to noxious mechanical stimulation within the same subjects. Further studies are needed to determine the anti-PDN effect of TZDs in humans.
authors.affiliation: Department of Physiology, College of Medicine, University of Kentucky Medical Center, Lexington, Kentucky.
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Griggs
authors.affiliation: Department of Physiology, College of Medicine, University of Kentucky Medical Center, Lexington, Kentucky.
authors.forename: Renee R
authors.initials: RR
authors.lastname: Donahue
authors.affiliation: Department of Physiology, College of Medicine, University of Kentucky Medical Center, Lexington, Kentucky.
authors.forename: Braxton G
authors.initials: BG
authors.lastname: Adkins
authors.affiliation: Department of Pharmacology and Nutritional Science, College of Medicine, University of Kentucky Medical Center, Lexington, Kentucky.
authors.forename: Katie L
authors.initials: KL
authors.lastname: Anderson
authors.affiliation: Department of Pharmacology and Nutritional Science, College of Medicine, University of Kentucky Medical Center, Lexington, Kentucky.
authors.forename: Olivier
authors.initials: O
authors.lastname: Thibault
authors.affiliation: Department of Physiology, College of Medicine, University of Kentucky Medical Center, Lexington, Kentucky. Electronic address: brad.taylor@uky.edu.
authors.forename: Bradley K
authors.initials: BK
authors.lastname: Taylor
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D059333:Central Nervous System Sensitization / Q000187:drug effects / Q000502:physiology; D003080:Cold Temperature; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000503:physiopathology; D004353:Drug Evaluation, Preclinical; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006358:Hot Temperature; D006930:Hyperalgesia / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D059226:Nociceptive Pain / Q000188:drug therapy / Q000503:physiopathology; D010766:Phosphorylation; D000077205:Pioglitazone; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000502:physiology; D011924:Rats, Zucker; D045162:Thiazolidinediones / Q000494:pharmacology*; D014110:Touch
chemical_list: D000700:Analgesics; D045162:Thiazolidinediones; D048049:Extracellular Signal-Regulated MAP Kinases; D000077205:Pioglitazone
keywords: Zucker Diabetic Fatty rat; neuropathic pain; painful diabetic neuropathy; peroxisome proliferator-activated receptor gamma