Laboratory of Nutrition and Development, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.
Neuroscience Research Institute, Peking University, Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory for Neuroscience, Ministry of Education of China & National Health Commission of China, Beijing 100191, China.
Brain Behav Immun. 2022 Oct;105:204-224. doi: 10.1016/j.bbi.2022.07.010. Epub 2022 Jul 16.
Sciatic nerve block is under investigation as a possible therapeutic strategy for neonatal injury-induced exaggeration of pain responses to reinjury. Spinal microglial priming, brain-derived neurotrophic factor (BDNF) and Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) participate in exaggerated incisional pain induced by neonatal incision. However, effects of sciatic nerve block on exacerbated incisional pain and underlying mechanisms remain unclear. Here, we demonstrated that sciatic nerve block alleviates pain hypersensitivity and microglial activation in rats subjected to neonatal incision and adult incision (nIN-IN). Chemogenetic activation or inhibition of spinal microglia attenuates or mimics effects of sciatic nerve block on pain hypersensitivity, respectively. Moreover, α-amino-3-hydroxy- 5-methy- 4-isoxazole propionate (AMPA) receptor subunit GluA1 contributes to the exaggeration of incisional pain. The inhibition of BDNF or SHP2 blocks upregulations of downstream molecules in nIN-IN rats. Knockdown of SHP2 attenuates the increase of GluA1 induced by injection of BDNF in adult rats with only neonatal incision. The inhibition of microglia or ablation of microglial BDNF attenuates upregulations of SHP2 and GluA1. Additionally, sciatic nerve block downregulates the expression of these three molecules. Upregulation of BDNF, SHP2 or AMPA receptor attenuates sciatic nerve block-induced reductions of downstream molecules and pain hypersensitivity. Microglial activation abrogates reductions of these three molecules induced by sciatic nerve block. These results suggest that decreased activation of spinal microglia contributes to beneficial effects of sciatic nerve block on the neonatal incision-induced exaggeration of incisional pain via downregulating BDNF/SHP2/GluA1-containing AMPA receptor signaling. Thus, sciatic nerve block may be a promising therapy.
坐骨神经阻滞作为一种可能的治疗策略，正在被研究用于治疗新生儿损伤引起的疼痛反应对再损伤的夸大。脊髓小胶质细胞的启动、脑源性神经营养因子（BDNF）和含 Src 同源-2 结构域蛋白酪氨酸磷酸酶-2（SHP2）参与了新生儿切口引起的切口痛的夸大。然而，坐骨神经阻滞对加剧的切口痛的影响及其潜在机制尚不清楚。在这里，我们证明坐骨神经阻滞减轻了新生儿切口和成人切口（nIN-IN）大鼠的疼痛过敏和小胶质细胞激活。脊髓小胶质细胞的化学遗传激活或抑制分别减弱或模拟坐骨神经阻滞对疼痛过敏的作用。此外，α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体亚基 GluA1 有助于切口痛的夸大。BDNF 或 SHP2 的抑制阻断了 nIN-IN 大鼠下游分子的上调。仅在新生儿切口的成年大鼠中，SHP2 的敲低减弱了 BDNF 注射引起的 GluA1 的增加。小胶质细胞的抑制或小胶质细胞 BDNF 的消融减弱了 SHP2 和 GluA1 的上调。此外，坐骨神经阻滞下调了这三个分子的表达。BDNF、SHP2 或 AMPA 受体的上调减弱了坐骨神经阻滞诱导的下游分子和疼痛过敏的降低。小胶质细胞的激活消除了坐骨神经阻滞引起的这三个分子的降低。这些结果表明，脊髓小胶质细胞的激活减少有助于坐骨神经阻滞对新生儿切口引起的切口痛夸大的有益作用，通过下调 BDNF/SHP2/GluA1 包含的 AMPA 受体信号。因此，坐骨神经阻滞可能是一种有前途的治疗方法。
