High-mobility group box 1-mediated microglial activation induces anxiodepressive-like behaviors in mice with neuropathic pain

Kazue Hisaoka-Nakashima, Yoshiaki Tomimura, Toshiki Yoshii, Kazuto Ohata, Naoki Takada, Fang Fang Zhang, Yoki Nakamura, Keyue Liu, Hidenori Wake, Masahiro Nishibori, Yoshihiro Nakata, Norimitsu Morioka

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)


Clinical evidence indicates that major depression is a common comorbidity of chronic pain, including neuropathic pain. However, the cellular basis for chronic pain-mediated major depression remains unclear. High-mobility group box 1 protein (HMGB1) has a key role in innate immune responses and appears to be have a role in mediating diverse disorders, including neuropathic pain and depression. The current study aimed to characterize neuropathic pain-induced changes in affect over time and to determine whether HMGB1 has a role in neuropathic pain-induced changes in affect. Neuropathic pain was induced by partial sciatic nerve ligation (PSNL) in mice. Anxiodepressive-like behaviors in mice were evaluated over 10 weeks, in the social interaction, forced swim, and novelty suppressed feeding tests. Mice developed anxiodepressive-like behavior 6 to 8 weeks after induction of neuropathy. Accompanying anxiodepressive-like behavior, increased HMGB1 protein and microglia activation were observed in frontal cortex at 8 weeks after PSNL. Intracerebroventricular administration of rHMGB1 in naïve mice induced anxiodepressive-like behavior and microglia activation. Blockage of HMGB1 in PSNL mice with glycyrrhizic acid (GZA) or anti-HMGB1 antibody reduced microglia activation and anxiodepressive-like behavior. These results indicate that PSNL-induced anxiodepressive-like behavior is likely mediated by HMGB1. Furthermore, the data indicate that inhibition of HMGB1-dependent microglia activation could be a strategy for the treatment of depression associated with neuropathic pain.

Original languageEnglish
Pages (from-to)347-362
Number of pages16
JournalProgress in Neuro-Psychopharmacology and Biological Psychiatry
Publication statusPublished - Jun 8 2019


  • Depression
  • HMGB1
  • Microglia
  • Neuropathic pain

ASJC Scopus subject areas

  • Pharmacology
  • Biological Psychiatry


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