Department of Pharmacology, Hiroshima University Graduate School of Biomedical and Health Sciences, Japan.
Department of Pharmacology, Hiroshima University Graduate School of Biomedical and Health Sciences, Japan; Institute of Pharmacology, Taishan Medical University.
Biochem Pharmacol. 2021 Apr;186:114496. doi: 10.1016/j.bcp.2021.114496. Epub 2021 Mar 3.
High mobility box 1 (HMGB1), a damage-associated molecular pattern, has crucial roles in induction of neuropathic pain. Upregulation of HMGB1 around the injured sciatic nerve contributes to mechanical hypersensitivity following partial sciatic nerve ligation (PSNL) of mice. However, central mechanisms mediating perineural HMGB1-induced nociceptive hypersensitivity, especially within the spinal dorsal horn, have not been determined. The current study shows that perineural treatment of naïve mice with recombinant HMGB1, which mimics increased HMGB1 around the injured sciatic nerve of PSNL mice, significantly induced activation of microglia, but not astrocytes, in the spinal dorsal horn. Intraperitoneal injection of minocycline, a microglial inhibitor, ameliorated perineural rHMGB1-induced mechanical hypersensitivity. In addition, blockade of spinal N-methyl-D-aspartate (NMDA) receptors significantly prevented perineural rHMGB1-induced mechanical hypersensitivity and microglial activation. In contrast, non-NMDA receptors, neurokinin 1 receptor, colony-stimulating factor 1 receptor and P2Y receptor were not involved in perineural rHMGB1-induced mechanical hypersensitivity. Furthermore, repeated perineural treatment with an anti-HMGB1 antibody blocked activation of spinal microglia in PSNL mice. Collectively, the current findings demonstrate that increased HMGB1 around injured sciatic nerve might induce nociceptive hypersensitivity through activation of spinal microglia. Thus, HMGB1-dependent mechanisms between the injured sciatic nerve and spinal dorsal horn could be crucial in induction of neuropathic pain.
高迁移率族蛋白 B1（HMGB1）是一种损伤相关分子模式，在诱导神经性疼痛中起关键作用。在小鼠部分坐骨神经结扎（PSNL）后，损伤的坐骨神经周围 HMGB1 的上调导致机械性超敏反应。然而，介导神经周围 HMGB1 诱导的痛觉过敏的中枢机制，特别是在脊髓背角内，尚未确定。本研究表明，对 naïve 小鼠进行神经周围重组 HMGB1（模拟 PSNL 小鼠损伤坐骨神经周围增加的 HMGB1）处理，可显著激活脊髓背角中的小胶质细胞，但不会激活星形胶质细胞。腹腔内注射小胶质细胞抑制剂米诺环素可改善神经周围 rHMGB1 诱导的机械性超敏反应。此外，阻断脊髓 N-甲基-D-天冬氨酸（NMDA）受体可显著预防神经周围 rHMGB1 诱导的机械性超敏反应和小胶质细胞激活。相比之下，非 NMDA 受体、神经激肽 1 受体、集落刺激因子 1 受体和 P2Y 受体不参与神经周围 rHMGB1 诱导的机械性超敏反应。此外，反复神经周围给予抗 HMGB1 抗体可阻断 PSNL 小鼠脊髓小胶质细胞的激活。总之，目前的研究结果表明，损伤的坐骨神经周围增加的 HMGB1 可能通过激活脊髓小胶质细胞引起痛觉过敏。因此，损伤的坐骨神经和脊髓背角之间的 HMGB1 依赖性机制可能在诱导神经性疼痛中起关键作用。
