Longitudinal Study of Painful Diabetic Neuropathy in the Zucker Diabetic Fatty Rat Model of Type 2 Diabetes: Impaired Basal G-Protein Activity Appears to Underpin Marked Morphine Hyposensitivity at 6 Months

Abstract

Epidemiological studies in patients with type 1 and type 2 diabetes show that hyperglycemia is associated with the development of long-term microvascular complications, including painful diabetic neuropathy (PDN). However, as the prevalence of type 2 diabetes in humans far exceeds that of type 1, the present study was undertaken as a 22-week longitudinal investigation commencing at 7 weeks of age, to assess the utility of the Zucker diabetic fatty (ZDF) rat model of type 2 diabetes for the study of PDN. Behavioral methods were used to characterize temporal changes in hindpaw sensitivity as well as morphine potency in these animals. The effect of long-term diabetes on µ-opioid receptor function and mRNA expression levels in the spinal cord was also assessed. Diabetes developed spontaneously in ZDF rats with marked hyperglycemia (blood glucose levels ≥15 mM) evident by 11 weeks of age, which was maintained until study completion at 29 weeks. In ZDF rats, there was progressive development of mechanical allodynia in the hindpaws such that it was fully developed by 6 months of age. Concurrently, there was temporal loss of opioid sensitivity in these animals such that marked morphine hyposensitivity was evident at 6 months. In the spinal cord, basal G-protein function was significantly impaired at 29 weeks of age, resulting in apparently reduced agonist-stimulated µ-opioid receptor function compared with the prediabetic state. Together, our findings suggest that impaired basal G-protein activity underpins morphine hyposensitivity in PDN. Clinical management of diabetic neuropathic pain has been challenging. This study provides a mechanistic explanation regarding the effectiveness, or lack thereof, of opioid analgesia in the treatment of diabetic neuropathic pain.