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Spinal high‐mobility group box‐1 induces long‐lasting mechanical hypersensitivity through the toll‐like receptor 4 and upregulation of interleukin‐1β in activated astrocytes
Author(s) -
Morioka Norimitsu,
Miyauchi Kazuki,
Miyashita Keita,
Kochi Takahiro,
Zhang Fang Fang,
Nakamura Yoki,
Liu Keyue,
Wake Hidenori,
HisaokaNakashima Kazue,
Nishibori Masahiro,
Nakata Yoshihiro
Publication year - 2019
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14812
Subject(s) - hmgb1 , astrocyte , downregulation and upregulation , spinal cord , tlr4 , neuropathic pain , receptor , pharmacology , medicine , glutamate receptor , chemistry , immunology , endocrinology , central nervous system , biochemistry , psychiatry , gene
Intrathecal treatment with recombinant high‐mobility group box‐1 (rHMGB1) in naïve mice leads to a persistent and significantly decreased hind paw withdrawal threshold to mechanical stimuli, suggesting that spinal HMGB1 evokes abnormal pain processing. By contrast, repeated intrathecal treatment with anti‐HMGB1 antibody significantly reverses hind paw mechano‐hypersensitivity in mice with a partial sciatic nerve ligation (PSNL). By contrast, the cellular mechanism by which spinal HMGB1 induces neuropathic pain has yet to be fully elaborated. The current study tested the hypothesis that spinal HMGB1 could induce mechanical hypersensitivity through the activation of specific receptor in glial cells. Intrathecal pretreatment with toll‐like receptor (TLR) 4 inhibitors, but not TLR5, receptor for advanced glycation end‐products and C‐X‐C chemokine receptor type 4 inhibitors, prevented rHMGB1‐evoked mechanical hypersensitivity. Activation of spinal astrocytes appears to be crucial for the mechanism of action of rHMGB1 in naïve mice, as intrathecal pretreatment with astrocytic inhibitors prevented the rHMGB1‐induced mechanical hypersensitivity. Interleukin‐1β (IL‐1β) was up‐regulated within activated astrocytes and block of TLR4 prevented the upregulation of IL‐1β. Interleukin‐1β appears to be secreted by activated astrocytes, as IL‐1β neutralizing antibody prevented rHMGB1‐induced mechanical hypersensitivity. Furthermore, intrathecal pretreatment with either MK801 or gabapentin prevented the rHMGB1‐induced mechanical hypersensitivity, suggesting roles for spinal glutamate and the N ‐methyl‐ d ‐aspartate receptor in the mediation of rHMGB1‐induced mechanical hypersensitivity. Thus, the current findings suggest that spinal HMGB1 upregulates IL‐1β in spinal astrocytes through a TLR4‐dependent pathway and increases glutamatergic nociceptive transduction. These spinal mechanisms could be key steps that maintain neuropathic pain.