<p>Diabetes mellitus significantly impacts perioperative anesthetic management. Patients with diabetic neuropathy exhibit increased sensitivity to local anesthetics, yet the underlying mechanisms, particularly regarding the median effective dose (ED₅₀) of ropivacaine and the role of voltage-gated sodium channels (Navs), remain incompletely elucidated. This study investigated the role of Navs in mediating the ED₅₀ of ropivacaine in streptozotocin (STZ)-induced diabetic rats. Using the Dixon up-and-down method, the ED₅₀ for sciatic nerve motor block was significantly lower in diabetic rats (0.100%) than in controls (0.142%), indicating heightened local anesthetic sensitivity. This pharmacodynamic shift was associated with underlying neuropathic changes, including reduced motor nerve conduction velocity (MNCV), decreased axon density, and downregulated expression of key Nav subtypes (Nav1.7, Nav1.8, Nav1.9) and the contactin-associated protein (CASPR) in the sciatic nerve and dorsal root ganglia (DRG). Crucially, administration of ropivacaine at the identified ED₅₀ dose did not exacerbate neurophysiological dysfunction, histological damage, or alter Navs/CASPR expression in diabetic nerves compared with saline-treated diabetic group, demonstrating a favorable safety profile. These findings elucidate the mechanism underlying reduced local anesthetic requirements in diabetic neuropathy, which involves Navs downregulation and structural nerve alterations, and support the clinical use of lower, effective ropivacaine doses in diabetic patients to achieve successful analgesia without increasing neurotoxicity risk.</p>