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 ∼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.