An LPA Species (18:1 LPA) Plays Key Roles in the Self-Amplification of Spinal LPA Production in the Peripheral Neuropathic Pain Model

Abstract

BackgroundWe previously reported that nerve injury-induced neuropathic pain is initiated by newly produced lysophosphatidic acid (LPA).ResultsIn this study, we developed a quantitative mass spectrometry for detecting LPA species by using Phos-tag. Following nerve injury, the levels of 18:1, 16:0 and 18:0 LPA in the spinal dorsal horn significantly increased at 3 h and declined at 6 h. Among them, 18:1 LPA level was the most abundant. In the same preparation, there were significant elevations in the activities of cytosolic phospholipase A2 (cPLA2) and calcium-independent phospholipase A2 (iPLA2), key enzymes for LPA synthesis, at 1 h, while there was no significant change in phospholipase A1 activity. Pharmacological studies revealed that NMDA and neurokinin 1 receptors, cPLA2, iPLA2 and microglial activation, as well as LPA1 and LPA3 receptors were all involved in the nerve injury-induced LPA production, and underlying cPLA2 and iPLA2 activations. In the cells expressing LPA1 or LPA3 receptor, the receptor-mediated calcium mobilization was most potent with 18:1 LPA, compared with 16:0 or 18:0 LPA. Moreover, the intrathecal injection of 18:1 LPA, but not 16:0 or 18:0 LPA, caused a spinal LPA production and neuropathic pain-like behavior.ConclusionThese results suggest that 18:1 LPA is the predominant ligand responsible for LPA1 and LPA3 receptors-mediated amplification of LPA production through microglial activation.

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

“…Transactivation of EGFR signaling (e.g., via LPAR1, which is expressed by astrocytes) (Fig. 9B) induces increased expression of cytosolic phospholipase A2 (cPLA2) enzymes (58)(59)(60)(61). In our gene expression data, the cPLA2 enzyme Pla2g4a was upregulated by 1.476-fold in early glaucoma (stage 1b; P = 0.0004), and RNA in situ hybridization revealed its expression by astrocytes in the ONH (Fig.…”

LPA receptor signaling: pharmacology, physiology, and pathophysiology

“…In addition, LPA and ATX levels not by 16:0 LPA or 18:0 LPA (223). Interestingly, intraperitoneal administration of Ki16425 (LPA 1/3 antagonist) within a short window straddling the induction of pain appears to completely block LPA-induced nociception (223). These proof-of-concept studies indicate that LPA and LPA 1 signaling can serve as important therapeutic targets for myelinating diseases, including neuropathic pain.…”

Lysophosphatidic acid receptors (LPARs): Potential targets for the treatment of neuropathic pain

“…LPA also activates PLC via the Gα q/11 and Gα i/o coupled LPAR 3 subtype. Notably, there is minimal LPA production in Lpar1 -/-and Lpar3 -/-mice and NP is abolished in this phenotype (Ma et al, 2013;Ma et al, 2009b), suggesting that both receptors mediate the amplification of LPA production, which is necessary to induce NP. Supporting these findings are reports that the chemotherapeutic drug, paclitaxel, triggers NP in mice by stimulating LPAR 1 -and LPAR 3 -mediated LPA production (Uchida et al, 2014).…”

“…Blockade of both NMDA and NK1 receptors prior to nerve injury by their respective antagonists, MK-801 and CP-99994, resulted in the inhibition of LPA production at the dorsal horn (Ma et al, 2013). This suggests that nerve injury results in glutamate and substance P-mediated activation of NMDA and NK1 receptors on neurons and subsequent activation of the enzyme PLA 2 leading to LPA production and initiation of neuropathic pain (see Figure 2).…”

“…LPA causes an increase in expression of brain-derived neurotrophic factor (BDNF) in primary cultures of rat microglia which express LPAR 3 (Fujita et al, 2008). LPA activates macrophages/microglia, possibly through LPAR 1 and LPAR 3 , and this initiates a self-sustaining feedforward loop of LPA production within macrophages/microglia, which can be inhibited with minocycline (Ma et al, 2013;Uchida et al, 2014). Moreover, intrathecal injection of mice with LPA increases the transcription of genes such as CD11b, leading to activation of microglia and morphological changes from ramified to amoeboid phenotypes.…”