Diabetic Neuropathic Pain Models: Current Limitations and Future Directions

Abstract: Diabetic neuropathic pain (DNP) is a disabling complication of diabetes, yet pain develops only in a subset of patients with diabetic neuropathy. Current animal models can reproduce hyperglycemia and many structural, electrophysiological, and metabolic features of diabetic neuropathy, but pain-related phenotypes vary considerably across studies. This variability may arise from methodological differences in model induction, experimental conditions, and behavioral assessment, but may also reflect biologically meaningful heterogeneity analogous to the painful and painless phenotypes observed clinically. This narrative review critically examines the strengths and limitations of commonly used streptozotocin (STZ), genetic, and high-fat diet/STZ models, with particular attention to variability in pain-related phenotypes and its implications for model interpretation. Species, strain, sex, disease duration, metabolic severity, model induction, and behavioral methodology may all contribute to differences among studies. On the basis of this synthesis, we suggest that future studies distinguish methodological variability from biological heterogeneity and use more consistent reporting, longitudinal assessment, and complementary measures of neuropathy to improve interpretation and clinical relevance. Keywords: diabetic neuropathic pain, animal models, reproducibility, phenotypic heterogeneity, translational validity, neuropathy