Interleukin-1β Plays Key Roles in LPA-Induced Amplification of LPA Production in Neuropathic Pain Model

Lysophosphatidic acid (LPA) is a bioactive lipid mediator that exerts a wide range of biological actions. In recent decades, LPA has been demonstrated as an important initiator of neuropathic pain based on the mechanisms of LPA-induced feed-forward LPA amplification. In this study, we examined the possible involvement of interleukin (IL)-1 beta in such LPA production. Intrathecal (i.t.) LPA injection rapidly increased the expression of IL-1 beta mRNA in the spinal dorsal horn as early as 0.5 h after injection, and the level reached peak at 2 h. Through a developed quantitative mass spectrometry for detecting LPA species, the elevated levels of 18:1, 16:0, and 18:0 LPA in the spinal dorsal horn were observed at 3 h after 18:1 LPA injection and this elevation was completely blocked by the pretreatment of IL-1 beta-neutralizing antibody. Moreover, enzyme assay experiments showed that LPA (i.t.) significantly activated calcium-independent phospholipase A(2) (iPLA(2)) and cytosolic phospholipase A(2) (cPLA(2)) in the spinal dorsal horn at 1 and 2 h, respectively, and these biochemical changes were also significantly inhibited by IL-1 beta-neutralizing antibody. Similarly, IL-1 beta-neutralizing antibody reversed LPA-induced neuropathic pain-like behavior. These findings suggest that the early release of IL-1 beta is involved in LPA-induced amplification of LPA production, which underlies the initial mechanisms of LPA-induced neuropathic pain.