Pioglitazone Inhibits the Development of Hyperalgesia and Sensitization of Spinal Nociresponsive Neurons in Type 2 Diabetes

• A genetic rat model of type 2 diabetes exhibited signs of affective pain.
• Central sensitization of dorsal horn neurons coincided with mechanical hyperalgesia.
• Pioglitazone inhibited hyperalgesia and central sensitization in type 2 diabetes.
• Thiazolidinediones might alleviate type 2 diabetes-associated pain in patients.

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 (ZDFfa/fa [ZDF]) rats. Compared with Zucker Lean (ZLfa/+) 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.PerspectiveTo 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.