Lysophosphatidic acid-3 receptor-mediated feed-forward production of lysophosphatidic acid: An initiator of nerve injury-induced neuropathic pain

Background: We previously reported that intrathecal injection of lysophosphatidylcholine (LPC) induced neuropathic pain through activation of the lysophosphatidic acid (LPA)-1 receptor, possibly via conversion to LPA by autotaxin (ATX).Results: We examined in vivo LPA-induced LPA production using a biological titration assay with B103 cells expressing LPA ₁ receptors. Intrathecal administration of LPC caused time-related production of LPA in the spinal dorsal horn and dorsal roots, but not in the dorsal root ganglion, spinal nerve or sciatic nerve. LPC-induced LPA production was markedly diminished in ATX heterozygotes, and was abolished in mice that were deficient in LPA ₃, but not LPA ₁ or LPA ₂ receptors. Similar time-related and LPA ₃ receptor-mediated production of LPA was observed following intrathecal administration of LPA. In an in vitro study using spinal cord slices, LPA-induced LPA production was also mediated by ATX and the LPA ₃ receptor. Intrathecal administration of LPA, in contrast, induced neuropathic pain, which was abolished in mice deficient in LPA ₁ or LPA ₃ receptors.Conclusion: These findings suggest that feed-forward LPA production is involved in LPA-induced neuropathic pain.