Insulin Implants Prevent the Temporal Development of Mechanical Allodynia and Opioid Hyposensitivity for 24-Wks in Streptozotocin (STZ)-Diabetic Wistar Rats

Objective. As the Diabetes Control and Complications Trial showed that intensive glycemic control in patients with Type 1 diabetes decreased the risk of development of long-term microvascular complications including painful diabetic neuropathy by similar to 60%, hyperglycemia was implicated as a causal factor in the etiology of this condition. Hence, the present study was designed as a 24-week longitudinal investigation of the extent to which the level of glycemic control in the streptozotocin (STZ)-diabetic rat model of Type 1 diabetes affects the development of mechanical allodynia and opioid hyposensitivity in these animals. Results. Diabetes was fully developed (blood glucose levels >= 15 mM) in adult male Wistar rats by 7 days after intravenous STZ (75 mg/kg) administration. Mechanical allodynia developed in a temporal manner in the rat hindpaws, such that it was fully developed by 6 weeks and persisted for at least 24 weeks post-STZ administration. Morphine hyposensitivity also developed in a temporal manner in the same animals. By contrast, restoration and maintenance of euglycemia using insulin implants commencing at diabetes diagnosis on Day 7 post-streptozotocin administration, prevented development of both mechanical allodynia and opioid hyposensitivity in STZ-diabetic rats for the 24-week study duration. Conclusions. This study shows that long-term restoration of euglycemia over a 6-month period in STZ-diabetic rats prevents the hallmark symptoms of PDN including morphine hyposensitivity. Clinical Relevance. Our findings are consistent with epidemiological data showing that tight glycemic control in patients with Type 1 diabetes markedly reduces the prevalence of PDN, further implicating persistent hyperglycemia as a pathogenic factor.