Lysophosphatidic Acid and its Receptors LPA₁ and LPA₃ Mediate Paclitaxel-Induced Neuropathic Pain in Mice

Abstract

BackgroundPaclitaxel, which is widely used for the treatment of solid tumors, causes neuropathic pain via poorly understood mechanisms. Previously, we have demonstrated that lysophosphatidic acid (LPA) and its receptors (LPA1 and LPA3) are required for the initiation of peripheral nerve injury-induced neuropathic pain. The present study aimed to clarify whether LPA and its receptors could mediate paclitaxel-induced neuropathic pain.ResultsIntraperitoneal administration of paclitaxel triggered a marked increase in production of LPA species (18:1-, 16:0-, and 18:0-LPA) in the spinal dorsal horn. Also, we found significant activations of spinal cytosolic phospholipase A2 and calcium-independent phospholipase A2 after the paclitaxel treatment. The paclitaxel-induced LPA production was completely abolished not only by intrathecal pretreatment with neurokinin 1 (NK1) or N-methyl-D-aspartate (NMDA) receptor antagonist, but also in LPA1 receptor-deficient (Lpar1−/−) and LPA3 receptor-deficient (Lpar3−/−) mice. In addition, the pharmacological blockade of NK1 or NMDA receptor prevented a reduction in the paw withdrawal threshold against mechanical stimulation after paclitaxel treatments. Importantly, the paclitaxel-induced mechanical allodynia was absent in Lpar1−/− and Lpar3−/− mice.ConclusionsThese results suggest that LPA1 and LPA3 receptors-mediated amplification of spinal LPA production is required for the development of paclitaxel-induced neuropathic pain.

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

“…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).…”

“…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.…”

Inhibition of Connexin 43 and Phosphorylated NR2B in Spinal Astrocytes Attenuates Bone Cancer Pain in Mice

“…The control mice were received an equivolume injection of NS. The dose selection for CARB and MK801 was based on the results from our previous experiments and reports from the literatures (Yoon et al, 2013 ; Shen et al, 2014 ; Uchida et al, 2014 ). Ten mice were used for each experimental group.…”

Systems Pathology of Neuropathic Pain and Fibromyalgia

“…LPA 1 and LPA 3 Receptor Signaling Also Underlies Paclitaxel-Induced Neuropathic Pain Mechanisms There are many reports that chemotherapeutic agents represented by paclitaxel cause peripheral neuropathic pain. [50][51][52] This is a unique type of chronic pain, since this pain would potentially be treated in a prophylactic way. The abnormal microtubule assembly of paclitaxel is considered one of the molecular mechanisms underlying its toxicity.…”