Oxypeucedanin attenuates neuropathic pain in male mice via inhibiting lysophosphatidic acid receptor signaling.

Oxypeucedanin (OPD) showed anti-allodynia against neuropathic pain (NeuP) in our previous study. In the present study, we aimed to further investigate whether lysophosphatidic acid receptor (LPAR) signaling mediated OPD-induced antinociception against NeuP models. Single OPD treatment dose-dependently reduced pain hypersensitivity, and repeated OPD treatment maintained sustained antinociception without the development of tolerance. Importantly, OPD exhibited a significant curative effect on different stages of NeuP. ROCK and RhoA agonists prevented the therapeutic effect of OPD, while the inhibitors of LPAR, ROCK, and RhoA mimicked OPD-induced antinociception. Notably, OPD treatment attenuated the increases of LPA content and protein expression of LPAR1, RhoA, and p-MYPT1 (the activated substrate of ROCK) in NeuP model mice. However, spinal LPAR1 over-expression reversed these molecular changes and OPD-induced antinociception; gene silencing of LPAR1 displayed a similar effect of OPD. Collectively, our findings firstly evidenced that OPD produced antinociception against NeuP via inhibiting the spinal activation of LPAR1/RhoA/ROCK signaling pathway.