Naringin Attenuates Diabetic Neuropathic Pain and Modulates TRPV1-Related Ca2+ Dysregulation and MAPK/NF-ΚB Signaling

Background/Objectives:Diabetic neuropathic pain (DNP) is a common complication of diabetes characterized by sensory abnormalities, including mechanical allodynia and thermal hyperalgesia. This study aimed to investigate the effects of naringin on experimental DNP and evaluate its association with dorsal root ganglion (DRG) neuronal injury, TRPV1-related calcium imbalance, and inflammatory signaling.Methods:Primary rat DRG neurons were exposed to high-glucose/high-free-fatty-acid (HGHF) conditions (50 mM glucose and 0.60 mM free fatty acids) and treated with naringin (40 or 80 μM). Cell viability, apoptosis, intracellular Ca2+levels, gene/protein expression, and signaling changes were assessed using CCK-8 assay, Annexin V-FITC/PI flow cytometry, Fluo-4 AM imaging, qRT-PCR, and Western blotting. Male Sprague–Dawley rats were fed a high-fat/high-sucrose diet for 4 weeks, injected with streptozotocin (35 mg kg−1), and treated with naringin (50 mg kg−1day−1) by gavage for 2 weeks.Results:HGHF exposure increased neuronal injury, TRPV1 expression, intracellular Ca2+accumulation, and p38 MAPK/NF-κB signaling activation. Naringin attenuated these changes in vitro, with stronger effects observed at 80 μM. In DNP rats, naringin improved pain-related behaviors, partially alleviated metabolic abnormalities, reduced TRPV1 expression and serum IL-1β/TNF-α levels, and decreased phosphorylation of p38 MAPK, NF-κB p65, and ERK in DRGs.Conclusions:Naringin alleviated experimental DNP-associated behavioral and molecular abnormalities, suggesting potential protective effects involving neuronal injury, calcium regulation, and inflammatory responses.