• Nilesh M Agalave, Resti Rudjito, Alex Bersellini Farinotti, KhoonsariPayam EmamiPEDepartment of Physiology and Pharmacology, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden., Katalin Sandor, Yuki Nomura, Thomas A Szabo-Pardi, Carlos Morado Urbina, Vinko Palada, Theodore J Price, Erlandsson HarrisHelenaHDepartment of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden., Michael D Burton, Kim Kultima, and Camilla I Svensson.
• Department of Physiology and Pharmacology, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
• Pain. 2021 Feb 1; 162 (2): 446458446-458.

AbstractHigh mobility group box 1 protein (HMGB1) is increasingly regarded as an important player in the spinal regulation of chronic pain. Although it has been reported that HMGB1 induces spinal glial activation in a Toll-like receptor (TLR)4-dependent fashion, the aspect of sexual dimorphisms has not been thoroughly addressed. Here, we examined whether the action of TLR4-activating, partially reduced disulfide HMGB1 on microglia induces nociceptive behaviors in a sex-dependent manner. We found disulfide HMGB1 to equally increase microglial Iba1 immunoreactivity in lumbar spinal dorsal horn in male and female mice, but evoke higher cytokine and chemokine expression in primary microglial culture derived from males compared to females. Interestingly, TLR4 ablation in myeloid-derived cells, which include microglia, only protected male mice from developing HMGB1-induced mechanical hypersensitivity. Spinal administration of the glial inhibitor, minocycline, with disulfide HMGB1 also prevented pain-like behavior in male mice. To further explore sex difference, we examined the global spinal protein expression using liquid chromatography-mass spectrometry and found several antinociceptive and anti-inflammatory proteins to be upregulated in only male mice subjected to minocycline. One of the proteins elevated, alpha-1-antitrypsin, partially protected males but not females from developing HMGB1-induced pain. Targeting downstream proteins of alpha-1-antitrypsin failed to produce robust sex differences in pain-like behavior, suggesting that several proteins identified by liquid chromatography-mass spectrometry are required to modulate the effects. Taken together, the current study highlights the importance of mapping sex dimorphisms in pain mechanisms and point to processes potentially involved in the spinal antinociceptive effect of microglial inhibition in male mice.Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.

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