Dexmedetomidine alleviates diabetic neuropathic pain by inhibiting microglial activation via regulation of miR-618/P2Y12 pathway

Abstract

Purpose: To investigate the effect of dexmedetomidine on streptozotocin (STZ)-induced diabetic neuropathy pain (DNP) in rats and elucidate its mechanism of action. Methods: The DNP rat model was established by injecting STZ (70 mg/kg) following dexmedetomidine treatment. Next BV-2 cells were stimulated using lipopolysaccharide (LPS, 200 ng/mL) and then administered 20 μM dexmedetomidine. Blood glucose levels, body weight, and paw withdrawal threshold (PWT) were measured once a week in DNP rats. Transfection was performed, and luciferase reporter assay was used to verify microRNA (miR)-337 binding to Rap1A mRNA. Reverse transcriptionpolymerase chain reaction (RT-PCR) was used to measure the levels of miR-618 and P2Y12 while the protein levels of P2Y12 and ionized calcium-binding adaptor molecule 1 (IBA-1) were determined by western blot analysis. Results: Dexmedetomidine treatment significantly increased PWT (p < 0.01) in DNP rats and decreased miR-618 expression (p < 0.01) but increased P2Y12 expression (p < 0.01) in the spinal cord of DNP rats. Luciferase reporter assay data showed that the presumed binding site of miR-618 is located in the 3'-untranslated regions of P2Y12. MiR-618 overexpression significantly reduced P2Y12 levels (p < 0.01). Dexmedetomidine upregulated P2Y12 expression (p < 0.01) but decreased IBA-1 expression (p < 0.01). Conclusion: Dexmedetomidine application attenuates DNP by inhibiting microglial activation via the regulation of miR-618/P2Y12 pathway. This finding provides a potential therapeutic strategy for DNP management.