Modulation of Nav1.8 by Lysophosphatidic Acid in the Induction of Bone Cancer Pain

Given that lysophosphatidic acid (LPA) and the tetrodotoxin-resistant sodium channel Na(v)1.8 are both involved in bone cancer pain, the present study was designed to investigate whether crosstalk between the LPA receptor LPA(1) (also known as EDG2) and Na(v)1.8 in the dorsal root ganglion (DRG) contributes to the induction of bone cancer pain. We showed that the EDG2 antagonist Ki16198 blocked the mechanical allodynia induced by intrathecal LPA in na < ve rats and attenuated mechanical allodynia in a rat model of bone cancer. EDG2 and Na(v)1.8 expression in L4-6 DRGs was upregulated following intrathecal or hindpaw injection of LPA. EDG2 and Na(v)1.8 expression in ipsilateral L4-6 DRGs increased with the development of bone cancer. Furthermore, we showed that EDG2 co-localized with Na(v)1.8 and LPA remarkably enhanced Na(v)1.8 currents in DRG neurons, and this was blocked by either a protein kinase C (PKC) inhibitor or a PKC epsilon inhibitor. Overall, we demonstrated the modulation of Na(v)1.8 by LPA in DRG neurons, and that this probably underlies the peripheral mechanism by which bone cancer pain is induced.