title: Autotaxin, a synthetic enzyme of lysophosphatidic acid (LPA), mediates the induction of nerve-injured neuropathic pain.
abstract: Recently, we reported that lysophosphatidic acid (LPA) induces long-lasting mechanical allodynia and thermal hyperalgesia as well as demyelination and upregulation of pain-related proteins through one of its cognate receptors, LPA1. In addition, mice lacking the LPA1 receptor gene (lpa1-/- mice) lost these nerve injury-induced neuropathic pain behaviors and phenomena. However, since lpa1-/- mice did not exhibit any effects on the basal nociceptive threshold, it is possible that nerve injury-induced neuropathic pain and its machineries are initiated by LPA via defined biosynthetic pathways that involve multiple enzymes. Here, we attempted to clarify the involvement of a single synthetic enzyme of LPA known as autotaxin (ATX) in nerve injury-induced neuropathic pain. Wild-type mice with partial sciatic nerve injury showed robust mechanical allodynia starting from day 3 after the nerve injury and persisting for at least 14 days, along with thermal hyperalgesia. On the other hand, heterozygous mutant mice for the autotaxin gene (atx+/-), which have 50% ATX protein and 50% lysophospholipase D activity compared with wild-type mice, showed approximately 50% recovery of nerve injury-induced neuropathic pain. In addition, hypersensitization of myelinated Abeta or Adelta-fiber function following nerve injury was observed in electrical stimuli-induced paw withdrawal tests using a Neurometer. The hyperalgesia was completely abolished in lpa1-/- mice, and reduced by 50% in atx+/- mice. Taken together, these findings suggest that LPA biosynthesis through ATX is the source of LPA for LPA1 receptor-mediated neuropathic pain. Therefore, targeted inhibition of ATX-mediated LPA biosynthesis as well as LPA1 receptor and its downstream pathways may represent a novel way to prevent nerve injury-induced neuropathic pain.
authors.affiliation: Division of Molecular Pharmacology and Neuroscience, Nagasaki University, Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan. minoue@nagasaki-u.ac.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Inoue
authors.forename: Lin
authors.initials: L
authors.lastname: Ma
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ueda
mesh_terms: D000818:Animals; D006930:Hyperalgesia / Q000201:enzymology; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism*; D010147:Pain Measurement; D043264:Phosphodiesterase I / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases / Q000378:metabolism*; D012584:Sciatic Nerve / Q000201:enzymology* / Q000473:pathology*; D020426:Sciatic Neuropathy / Q000201:enzymology*; D000099189:Lysophospholipase D
chemical_list: D008246:Lysophospholipids; D009097:Multienzyme Complexes; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid