Objective: Despite the application of dexmedetomidine (DEX) as a perioperative adjuvant in local analgesia, the exact analgesic mechanism underpinning chronic neuropathic pain (CNP) awaits our elucidation. Methods: We investigated the molecular mechanisms of the anti-nociceptive effect of DEX on neuropathic pain in a mouse model induced by chronic constriction injury (CCI). Results: DEX administration significantly increased the paw withdrawal latency (PWL) values 0.5 to 2 h post-injection in CCI-induced CNP mice at day 5 to 21 versus dimethyl sulfoxide (DMSO)-treated mice, confirming its analgesic effect. The c-Fos expression was significantly elevated in CCI mice versus the sham-operated group, whereas the elevation was mitigated by DEX injection. Subsequently, the involvement of MKP1 and MKP3 in the pathogenesis of chronic neuropathic pain was evaluated. Western blotting analyses revealed significant decrease in both MKP1 and MKP3 in the spinal cord in CCI group versus the sham group. DEX markedly elevated the MKP3 expression and modestly reduced the MKP1 expression, with insignificant difference in the latter. Co-injection of BCI (an MKP3 inhibitor) and DEX evidently reduced the PWL values in CCI mice. Furthermore, DEX significantly downregulated the phosphorylation of extracellular-signal-regulated kinase (ERK) 1/2, down-stream effector of MKP3 in CCI mice, whereas the downregulation was reversed by BCI. Conclusion: We confirmed that DEX exerts the analgesic effect on chronic neuropathic pain via the regulation of MKP3/ERK1/2 signaling pathway, which may contribute to clarification of the molecular mechanism and novel therapy for chronic neuropathic pain.

中文翻译：

---

鞘内注射右美托咪定可通过调节慢性神经性疼痛小鼠模型中的MPK3 / ERK1 / 2改善慢性神经性疼痛。

目的：尽管右美托咪定（DEX）在局部镇痛中作为围手术期辅助剂的应用，但支持慢性神经性疼痛（CNP）的确切镇痛机制仍在等待我们的阐明。方法：我们研究了DEX对慢性收缩性损伤（CCI）所致小鼠模型神经痛的镇痛作用的分子机制。结果：与二甲基亚砜（DMSO）处理的小鼠相比，DEX注射在第5天至第21天注射CCI诱导的CNP小鼠后，爪回缩潜伏期（PWL）值显着增加了0.5至2 h，证实了其镇痛作用。与假手术组相比，CCI小鼠的c-Fos表达显着升高，而DEX注射可减轻c-Fos表达。后来，评估了MKP1和MKP3在慢性神经性疼痛发病机理中的作用。蛋白质印迹分析显示，与假手术组相比，CCI组的脊髓中MKP1和MKP3均显着降低。DEX显着提高了MKP3的表达，并适度降低了MKP1的表达，后者之间的差异不明显。BCI（一种MKP3抑制剂）和DEX的共同注射明显降低了CCI小鼠的PWL值。此外，DEX显着下调了CCI小鼠中MKP3下游效应物细胞外信号调节激酶（ERK）1/2的磷酸化，而BCI则逆转了这种下调。结论：我们证实DEX通过调节MKP3 / ERK1 / 2信号通路对慢性神经性疼痛具有镇痛作用，