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 luciferasereporter 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 P2Y12levels (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. Keywords: Dexmedetomidine, Diabetic neuropathy pain, Paw withdrawal threshold, Calcium-binding adaptor molecule 1, MiR-618, P2Y12

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Purpose: To elaborate the functional role of dexmedetomidine (DEX) in alleviating microglial activation of diabetic neuropathic pain (DNP) and explore the involved signaling pathways. Methods: The viability of BV-2 cells was measured using a commercial kit. Levels of interleukin 1β (IL- 1β) and tumor necrosis factor-α (TNF-α) were measured using commercial ELISA kit. The mRNA target was predicted and confirmed using TargetScan and luciferase assay. Protein expression levels were determined by western blotting. Diabetes was indiced in C57BL/6J mice using streptozotocin (STZ) and antidiabetic parameters evaluated in vivo. Results: DEX suppressed HG-induced microglial activation in BV-2 cells. The levels of IL-1β and TNF-α increased in HG-treated cells, but this was counteracted following DEX treatment. Phosphorylation of p65 (p-p65) was upregulated in cells treated with HG, while DEX repressed this upregulation. MiR-23a was downregulated in BV-2 cells treated with HG, but upregulated by addition of DEX. MiR-23a mimics repressed the induction of IL-1β and TNF-α levels and expression of p-p65. Results from TargetScan and luciferase assays showed that the 3-untranslated region (UTR) of PDE10A was directly targeted by miR-23a. The in vivo studies showed that miR-23a agomir relieved neuropathic pain and reduced the expressions of PDE10A and p-p65 in STZ-induced diabetic mice, but these effects were aggravated by DEX. Conclusion: The results show that upregulation of miR-23a, DEX alleviates microglial activation of neuropathic pain and reduces levels of inflammatory factors in STZ-induced diabetic C57BL/6J mice. The underlying mechanism was at least partially mediated by PDE10A.