title: Lysophosphatidic acid and its receptors LPA1 and LPA3 mediate paclitaxel-induced neuropathic pain in mice.
abstract: BACKGROUND
  Paclitaxel, 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.
  
  
  RESULTS
  Intraperitoneal 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.
  
  
  CONCLUSIONS
  These results suggest that LPA1 and LPA3 receptors-mediated amplification of spinal LPA production is required for the development of paclitaxel-induced neuropathic pain.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Uchida
authors.forename: Jun
authors.initials: J
authors.lastname: Nagai
authors.affiliation: 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.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ueda
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009437:Neuralgia / Q000139:chemically induced / Q000150:complications / Q000473:pathology; D017239:Paclitaxel / Q000633:toxicity*; D010147:Pain Measurement / Q000187:drug effects; D054467:Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D066148:Spinal Cord Dorsal Horn / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D008246:Lysophospholipids; D010880:Piperidines; D049368:Receptors, Lysophosphatidic Acid; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D016291:Dizocilpine Maleate; D054467:Phospholipases A2; D017239:Paclitaxel; C032881:lysophosphatidic acid