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Interleukin-1β Plays Key Roles in LPA-Induced Amplification of LPA Production in Neuropathic Pain Model

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Abstract

Lysophosphatidic acid (LPA) is a bioactive lipid mediator that exerts a wide range of biological actions. In recent decades, LPA has been demonstrated as an important initiator of neuropathic pain based on the mechanisms of LPA-induced feed-forward LPA amplification. In this study, we examined the possible involvement of interleukin (IL)-1β in such LPA production. Intrathecal (i.t.) LPA injection rapidly increased the expression of IL-1β mRNA in the spinal dorsal horn as early as 0.5 h after injection, and the level reached peak at 2 h. Through a developed quantitative mass spectrometry for detecting LPA species, the elevated levels of 18:1, 16:0, and 18:0 LPA in the spinal dorsal horn were observed at 3 h after 18:1 LPA injection and this elevation was completely blocked by the pretreatment of IL-1β-neutralizing antibody. Moreover, enzyme assay experiments showed that LPA (i.t.) significantly activated calcium-independent phospholipase A2 (iPLA2) and cytosolic phospholipase A2 (cPLA2) in the spinal dorsal horn at 1 and 2 h, respectively, and these biochemical changes were also significantly inhibited by IL-1β-neutralizing antibody. Similarly, IL-1β-neutralizing antibody reversed LPA-induced neuropathic pain-like behavior. These findings suggest that the early release of IL-1β is involved in LPA-induced amplification of LPA production, which underlies the initial mechanisms of LPA-induced neuropathic pain.

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Abbreviations

LPA:

Lysophosphatidic acid

DRG:

Dorsal root ganglion

i.t.:

Intrathecal

LPC:

Lysophosphatidylcholine

cPLA2 :

Cytosolic phospholipase A2

iPLA2 :

Calcium-independent phospholipase A2

IL-1β:

Interleukin-1β

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

MALDI-TOFMS:

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry

PLA1 :

Phospholipase A1

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Acknowledgments

We thank Prof. Akira Tokumura (Tokushima University) for the gift of LPA species (16:0, 17:0, 18:0, 20:4). We used these compounds as standards in the MALDI-TOFMS analysis in the preliminary experiments. This study was supported by Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (23116513 to H.U.), Grant-in-Aid for Young Scientists (B) (24790576 to J.N.), Ministry of Health, Labour and Welfare, the Tokyo Biomedical Research Foundation (2011 to H.U.), Ono Pharmaceutical Company Ltd and Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki, 852-8521, Japan

    Ryo Yano, Lin Ma, Jun Nagai & Hiroshi Ueda

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  1. Ryo Yano
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  2. Lin Ma
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  3. Jun Nagai
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  4. Hiroshi Ueda
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Corresponding author

Correspondence to Hiroshi Ueda.

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Ryo Yano, Lin Ma, and Jun Nagai contributed equally to this study.

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Yano, R., Ma, L., Nagai, J. et al. Interleukin-1β Plays Key Roles in LPA-Induced Amplification of LPA Production in Neuropathic Pain Model. Cell Mol Neurobiol 33, 1033–1041 (2013). https://doi.org/10.1007/s10571-013-9970-3

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