EXPRESS: Exploring circRNA_19601 as a therapeutic target in diabetic neuropathic pain: insights from rat and cell models

Background: Diabetic neuropathic pain (DNP) is a common complication of diabetes with significant impact on patients' quality of life. Current treatments have limitations, and exploring new mechanisms and targets is crucial. Objective: Our study aims to explore the role and mechanism of circRNA_19601 (circ19601) in regulating miR-324-5p in DNP within the dorsal root ganglion (DRG). Methods: This study used streptozotocin (STZ) and high-fat diet-induced diabetic rat models, as well as high-sugar treated DRG neurons to construct cell models. The STZ and high-fat diet induced a diabetic neuropathic pain model in rats, and high-glucose conditions were used to extract DRG neurons. The effects of the positive control drug pregabalin on STZ rats were monitored under different dosing conditions by measuring body weight, blood glucose, mechanical paw withdrawal threshold, and thermal paw withdrawal latency. The study also analyzed the expression of circular RNA in DRG neurons affected by diabetic neuropathic pain. Next, we also examined the effects of knocking down circ19601 with or without the miR-324-5p inhibitor on DNP. The expression of pain-related membrane proteins was analyzed using Western blot. Results: STZ treatment in diabetic rats led to reduced body weight, elevated blood glucose, and decreased pain sensitivity. Pregabalin effectively improved mechanical hyperalgesia but mainly influenced mechanical sensitivity long-term. Transcriptomic analysis revealed upregulation of circ19601 in diabetic rats, which was reversed by pregabalin. Knockdown of circ19601 improved body weight, reduced blood glucose, and alleviated pain sensitivity by increasing miR-324-5p levels and decreasing neurotransmitter and pain-related protein levels. MiR-324-5p inhibition reversed these effects, highlighting its role in regulating pain pathways in diabetic neuropathy. Conclusion: Pregabalin mitigates mechanical and thermal pain in diabetic rats. It does so by reversing decreased pain thresholds and modifying the expression of circ19601. This, in turn, impacts miR-324-5p and pain-related proteins, leading to improvements in body weight and blood glucose levels.