Relief from neuropathic pain by blocking of the platelet-activating factor-pain loop.
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.
Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan; hshindou-tky@umin.net.|Agency for Research and Medical Development (AMED), Tokyo Japan.|Department of Lipid Science, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Hideo
H
Shindou
Agency for Research and Medical Development (AMED), Tokyo Japan.|Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and.
Seiji
S
Shiraishi
Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and.
Suzumi M
SM
Tokuoka
Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan.
Yoshikazu
Y
Takahashi
Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan.
Takeshi
T
Harayama
Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe, Japan; and.
Takaya
T
Abe
Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe, Japan; and.|Animal Resource Development Unit, RIKEN Center for Life Science Technologies, Kobe, Japan; and.
Kana
K
Bando
Agency for Research and Medical Development (AMED), Tokyo Japan.|Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and.
Kanako
K
Miyano
Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and.|Life Sciences Core Facility, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Yoshihiro
Y
Kita
Agency for Research and Medical Development (AMED), Tokyo Japan.|Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.|Division of Supportive Care Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan.
Yasuhito
Y
Uezono
Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan.|Life Sciences Core Facility, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Takao
T
Shimizu
D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005786:Gene Expression Regulation / Q000502:physiology; D006930:Hyperalgesia; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia; D009437:Neuralgia / Q000188:drug therapy*; D010972:Platelet Activating Factor / Q000235:genetics / Q000378:metabolism*; D066148:Spinal Cord Dorsal Horn / Q000378:metabolism
D010972:Platelet Activating Factor; D008243:1-Acylglycerophosphocholine O-Acyltransferase; C000592232:LPCAT2 protein, mouse
LPCAT2; PAF; analgesic drug; feedback loop; lysophosphatidylcholine acyltransferase 2