Dehydrocorydaline alleviates sleep deprivation-induced persistent postoperative pain in adolescent mice through inhibiting microglial P2Y(12) receptor expression in the spinal cord.
Dehydrocorydaline alleviates sleep deprivation-induced persistent postoperative pain in adolescent mice through inhibiting microglial P2Y(12) receptor expression in the spinal cord.
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DOI：
10.1177/17448069231216234
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发表时间：
2023-01
期刊：
影响因子：
3.3
通讯作者：
中科院分区：
文献类型：
--
作者：
在青春期，中枢神经系统(CNS)在胎儿期之后的第二个可塑性时期变得明显，这涉及到睡眠剥夺(SD)。青春期的SD可能会导致神经回路的异常发育，导致神经元兴奋和抑制的失衡，这不仅会导致疼痛，而且会增加成年后发展成焦虑和抑郁等情绪障碍的机会。青春期手术的数量也在持续增加，但术前SD对术后疼痛的影响和潜在机制仍未被探索。本研究证明，术前SD可诱导脊髓小胶质细胞上表达的P2Y12受体上调，并使其下游信号通路p38MAPK/核转录因子-κB(p38MAPK/NF-κB)在脊髓小胶质细胞中磷酸化，从而促进小胶质细胞的激活和小胶质细胞向促炎性M1表型的转化，导致促炎细胞因子的表达增加，从而加剧青春期小鼠持续的术后切口痛。鞘内注射米诺环素(一种小胶质细胞激活抑制剂)和MRS2395(一种P2Y12受体阻滞剂)都有效地抑制了小胶质细胞的激活和促炎细胞因子的表达。有趣的是，补充延胡索提取物脱氢延胡索碱可抑制模型小鼠的P2Y12/p38MAPK/NF-κB信号通路、小胶质细胞的激活和促炎细胞因子的表达。以上结果表明，P2Y12受体和小胶质细胞的激活是青春期小鼠术前SD所致术后持续性疼痛的重要因素，DHC通过作用于这些靶点而具有镇痛作用。
During adolescence, a second period of central nervous system (CNS) plasticity that follows the fetal period, which involves sleep deprivation (SD), becomes apparent. SD during adolescence may result in abnormal development of neural circuits, causing imbalance in neuronal excitation and inhibition, which not only results in pain, but increases the chances of developing emotion disorders in adulthood, such as anxiety and depression. The quantity of surgeries during adolescence is also consistently on the rise, yet the impact and underlying mechanism of preoperative SD on postoperative pain remain unexplored. This study demonstrates that preoperative SD induces upregulation of the P2Y12 receptor, which is exclusively expressed on spinal microglia, and phosphorylation of its downstream signaling pathway p38Mitogen-activated protein/Nuclear transcription factor-κB (p38MAPK/NF-κB)in spinal microglia, thereby promoting microglia activation and microglial transformation into the proinflammatory M1 phenotype, resulting in increased expression of proinflammatory cytokines that exacerbate persisting postoperative incisional pain in adolescent mice. Both intrathecal minocycline (a microglia activation inhibitor) and MRS2395 (a P2Y12 receptor blocker) effectively suppressed microglial activation and proinflammatory cytokine expression. Interestingly, supplementation with dehydrocorydaline (DHC), an extract of Rhizoma Corydalis, inhibited the P2Y12/p38MAPK/NF-κB signaling pathway, microglia activation, and expression of pro-inflammatory cytokines in the model mice. Taken together, the results indicate that the P2Y12 receptor and microglial activation are important factors in persistent postoperative pain caused by preoperative SD in adolescent mice and that DHC has analgesic effects by acting on these targets.
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