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FASEB J. 2017 Jul;31(7):2973-2980. doi: 10.1096/fj.201601183R. Epub 2017 Mar 24.

Relief from neuropathic pain by blocking of the platelet-activating factor-pain loop.

Author information

1
Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan; hshindou-tky@umin.net.
2
Agency for Research and Medical Development (AMED), Tokyo Japan.
3
Department of Lipid Science, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
4
Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and.
5
Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan.
6
Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe, Japan; and.
7
Animal Resource Development Unit, RIKEN Center for Life Science Technologies, Kobe, Japan; and.
8
Life Sciences Core Facility, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
9
Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.
10
Division of Supportive Care Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan.

Abstract

Neuropathic pain resulting from peripheral neuronal damage is largely resistant to treatment with currently available analgesic drugs. Recently, ATP, lysophosphatidic acid, and platelet-activating factor (PAF) have been reported to play important inductive roles in neuropathic pain. In the present study, we found that pain-like behaviors resulting from partial sciatic nerve ligation (PSL) were largely attenuated by deficiency of lysophosphatidylcholine acyltransferase (LPCAT)2, which is one of the PAF biosynthetic enzymes. By contrast, deficiency of the other PAF biosynthetic enzyme, LPCAT1, did not ameliorate neuropathic pain. With regard to the mechanism of the observed effects, LPCAT2 was detected in wild-type spinal cord microglia, and the absence of LPCAT2 expression precluded spinal PAF expression in LPCAT2-knockout mice. Furthermore, ATP-stimulated PAF biosynthesis in macrophages was decreased by pretreatment with the PAF receptor antagonist ABT-491, indicating the existence of a positive feedback loop of PAF biosynthesis, which we designated the PAF-pain loop. In conclusion, LPCAT2 is a novel therapeutic target for newly categorized analgesic drugs; in addition, our data call for the re-evaluation of the clinical utility of PAF receptor antagonists.-Shindou, H., Shiraishi, S., Tokuoka, S. M., Takahashi Y., Harayama, T., Abe, T., Bando, K., Miyano, K., Kita, Y., Uezono, Y., Shimizu, T. Relief from neuropathic pain by blocking of the platelet-activating factor-pain loop.

KEYWORDS:

LPCAT2; PAF; analgesic drug; feedback loop; lysophosphatidylcholine acyltransferase 2

PMID:
28341636
PMCID:
PMC5471516
DOI:
10.1096/fj.201601183R
[Indexed for MEDLINE]
Free PMC Article

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