Simultaneous stimulation of spinal NK1 and NMDA receptors produces LPC which undergoes ATX-mediated conversion to LPA, an initiator of neuropathic pain

Makoto Inoue, Lin Ma, Junken Aoki, Hiroshi Ueda

Research output: Contribution to journalArticlepeer-review

Abstract

We previously reported that nerve injury-induced neuropathic pain and its underlying mechanisms are initiated by lysophosphatidic acid. In the present study, by measuring cell-rounding in a biological assay using lysophosphatidic acid 1 receptor-expressing B103 cells, we evaluated the molecular mechanism underlying lysophosphatidic acid biosynthesis following intense stimulation of primary afferents. Lysophosphatidic acid production was induced by treatment of spinal cord slices with capsaicin (10 μM), an intense stimulator of primary afferents, in the presence of recombinant autotaxin, but not in its absence. Lysophosphatidic acid was also induced by combination treatment of slices with high doses (10 and 30 μM) of substance P and NMDA, but not by other combinations of substance P, NMDA, calcitonin gene-related peptide and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (30 μM each) in the presence of recombinant autotaxin. We also found that following neurokinin 1 and NMDA receptor activation, activation of both cytosolic phospholipase A 2 and calcium-independent intracellular phospholipase A2 signalling pathways through protein kinase C and mitogen-activated protein/extracellular signal-regulated kinase activation and intracellular calcium elevation were required for lysophosphatidic acid production. These findings suggest that simultaneous intense stimulation of neurokinin 1 and NMDA receptors in the spinal dorsal horn triggers lysophosphatidic acid production from lysophosphatidylcholine through extracellular autotaxin.

Original languageEnglish (US)
Pages (from-to)1556-1565
Number of pages10
JournalJournal of Neurochemistry
Volume107
Issue number6
DOIs
StatePublished - Dec 2008
Externally publishedYes

Keywords

  • Autotaxin
  • Capsaicin
  • Lysophosphatidic acid
  • Lysophosphatidylcholine
  • Neuropathic pain
  • Spinal cord

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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