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J Neurochem. 2019 Jul 4. doi: 10.1111/jnc.14812. [Epub ahead of print]

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 information

1
Department of Pharmacology, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
2
Institute of Pharmacology, Taishan Medical University, 619 Changcheng Road, Taian, Shandong, 271016, China.
3
Cellular Pathobiology Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse IRP, Triad Suite 3305, 333 Cassell Drive, Baltimore, MD, 21224.
4
Department of Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1, Shikata, Okayama, 700-8558, Japan.

Abstract

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. Within activated astrocytes, interleukin-1β (IL-1β) was up-regulated, which was prevented with blockade of TLR4. 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. This article is protected by copyright. All rights reserved.

KEYWORDS:

HMGB1; TLR4; ainterleukin-1β; allodynia; glutamate; neuropathic pain

PMID:
31273787
DOI:
10.1111/jnc.14812

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