Research

Lysophosphatidic acid-3 receptor-mediated feed-forward production of lysophosphatidic acid: an initiator of nerve injury-induced neuropathic pain

Lin Ma¹ , Hitoshi Uchida¹ , Jun Nagai¹ , Makoto Inoue¹ , Jerold Chun² , Junken Aoki³ and Hiroshi Ueda¹

¹  Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan

²  Department of Molecular Biology, Helen L. Dorris Child and Adolescent Neuropsychiatric Disorder Institute, The Scripps Research Institute, 10550 North Torrey Pines Road, ICND118, La Jolla, CA 92037, USA

³  Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan

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Molecular Pain 2009, 5:64doi:10.1186/1744-8069-5-64

Published:	13 November 2009

Abstract

Background

We previously reported that intrathecal injection of lysophosphatidylcholine (LPC) induced neuropathic pain through activation of the lysophosphatidic acid (LPA)-1 receptor, possibly via conversion to LPA by autotaxin (ATX).

Results

We examined in vivo LPA-induced LPA production using a biological titration assay with B103 cells expressing LPA₁ receptors. Intrathecal administration of LPC caused time-related production of LPA in the spinal dorsal horn and dorsal roots, but not in the dorsal root ganglion, spinal nerve or sciatic nerve. LPC-induced LPA production was markedly diminished in ATX heterozygotes, and was abolished in mice that were deficient in LPA₃, but not LPA₁ or LPA₂ receptors. Similar time-related and LPA₃ receptor-mediated production of LPA was observed following intrathecal administration of LPA. In an in vitro study using spinal cord slices, LPA-induced LPA production was also mediated by ATX and the LPA₃ receptor. Intrathecal administration of LPA, in contrast, induced neuropathic pain, which was abolished in mice deficient in LPA₁ or LPA₃ receptors.

Conclusion

These findings suggest that feed-forward LPA production is involved in LPA-induced neuropathic pain.