Perineural high-mobility group box 1 induces mechanical hypersensitivity through activation of spinal microglia: Involvement of glutamate-NMDA receptor dependent mechanism in spinal dorsal horn

Yoki Nakamura, Ayako Fukuta, Keita Miyashita, Fang Fang Zhang, Dengli Wang, Keyue Liu, Hidenori Wake, Kazue Hisaoka-Nakashima, Masahiro Nishibori, Norimitsu Morioka

Research output: Contribution to journalArticlepeer-review

Abstract

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 P2Y12 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.

Original languageEnglish
Article number114496
JournalBiochemical Pharmacology
Volume186
DOIs
Publication statusPublished - Apr 2021

Keywords

  • Allodynia
  • HMGB1
  • Microglia
  • NMDA receptor
  • Neuropathic pain
  • Sciatic nerve

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Fingerprint Dive into the research topics of 'Perineural high-mobility group box 1 induces mechanical hypersensitivity through activation of spinal microglia: Involvement of glutamate-NMDA receptor dependent mechanism in spinal dorsal horn'. Together they form a unique fingerprint.

Cite this