• Mol Pain · Nov 2014

    Lysophosphatidic acid and its receptors LPA1 and LPA3 mediate paclitaxel-induced neuropathic pain in mice.

    • Hitoshi Uchida, Jun Nagai, and Hiroshi Ueda.
    • Department of Pharmacology and Therapeutic Innovation, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan. ueda@nagasaki-u.ac.jp.
    • Mol Pain. 2014 Jan 1;10:71.

    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.

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