Intravenous streptozotocin induces variants in painful diabetic peripheral neuropathy in female mice

Abstract Purpose: At least half of the 34 million diabetic patients in the U.S. develop painful diabetic peripheral neuropathy (DPN). Recent evidence suggests that there are sex differences in the prevalence and mechanisms underlying pathological pain states. However, due to technical limitations in murine models, there is a dearth of the use of females in diabetic neuropathy research. There is a need to develop a reproducible model to induce painful DPN in both sexes. The predominately used model employs streptozotocin (STZ) administration via intraperitoneal injections. This strategy consistently induces diabetic pathology in males, but not females. We set out to enhance a current murine DPN model by identifying a method for inducing diabetic pathologies in male and female mice and tracking the development of painful neuropathy. Methods: Painful DPN was induced in both male and female mice through five daily intravenous injections of STZ. Metrics of diabetic pathology and pain behaviors were assessed across the development of painful DPN. To investigate neuronal sensitivity, calcium imaging assessing dorsal root ganglia neurons was performed. Results: We found that after intravenous administration of STZ, both male and female mice exhibited elevated blood glucose levels, impaired glucose tolerance, and increased mechanical and thermal hypersensitivity. Interestingly, we observed a subset of STZ-insensitive animals that displayed comparable elevated glucose levels to the STZ-sensitive animals. Calcium imaging was performed to investigate neuronal sensitivity and we found that both male and female mice with diabetic pathology had a lower latency to peak capsaicin-induced response compared to their control counterparts. Conclusion: Our findings demonstrate that intravenous administration of STZ can induce comparable diabetic neuropathy in male and female mice and opens the door for future preclinical studies on diabetic neuropathy.