Secreted PLA2-III is a possible therapeutic target to treat neuropathic pain.

Lysophosphatidic acid (LPA) plays a critical role in developing and maintaining chronic pain in various animal models. Previous studies have reported that cytosolic and calcium-independent phospholipase A 2 (PLA 2) is involved in the LPA receptor-mediated amplification of LPA production in the spinal dorsal horn (SDH) after nerve injury, while the involvement of secreted PLA 2 (sPLA 2) remains unclear. The present study revealed that only sPLA 2 –III among 11 species of PLA 2 showed a significant upregulation of gene expression in the SDH. Intraspinal injection of adeno-associated virus-miRNA targeting sPLA 2 -III prevented hyperalgesia and unique hypoalgesia in mice treated with partial sciatic nerve ligation. In addition, intrathecal treatment with antisense oligodeoxynucleotide or siRNA targeting sPLA 2 -III significantly reversed the established thermal hyperalgesia. In the high-throughput screening of sPLA 2 -III inhibitors from the chemical library, we identified two hit compounds. Through in vitro characterization of PLA 2 inhibitor profiles and in vivo assessment of the anti-hyperalgesic effects of known PLA 2 inhibitors as well as hit compounds, sPLA 2 -III was found to be a novel therapeutic target molecule for the treatment of Neuropathic pain. • Selective upregulation of sPLA 2 -III gene expression was observed in the pSNL model. • Spinal sPLA 2 -III knockdown reversed the neuropathic pain. • HTS hit compounds showing sPLA 2 -III inhibition reversed the neuropathic pain. [ABSTRACT FROM AUTHOR]