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Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling

Nature Medicine volume 10, pages 712–718 (2004)Cite this article

An Erratum to this article was published on 01 July 2004

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Abstract

Lysophosphatidic acid (LPA) is a bioactive lipid with activity in the nervous system mediated by G-protein-coupled receptors. Here, we examined the role of LPA signaling in the development of neuropathic pain by pharmacological and genetic approaches, including the use of mice lacking the LPA1 receptor. Wild-type animals with nerve injury develop behavioral allodynia and hyperalgesia paralleled by demyelination in the dorsal root and increased expression of both the protein kinase C γ-isoform within the spinal cord dorsal horn and the α2δ1 calcium channel subunit in dorsal root ganglia. Intrathecal injection of LPA induced behavioral, morphological and biochemical changes similar to those observed after nerve ligation. In contrast, mice lacking a single LPA receptor (LPA1, also known as EDG2) that activates the Rho–Rho kinase pathway do not develop signs of neuropathic pain after peripheral nerve injury. Inhibitors of Rho and Rho kinase also prevented these signs of neuropathic pain. These results imply that receptor-mediated LPA signaling is crucial in the initiation of neuropathic pain.

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Figure 1: Induction of behavioral allodynia and hyperalgesia by exogenous LPA through the LPA1-RhoA-ROCK pathway.
Figure 2: Attenuated neuropathic pain after nerve injury in LPA1-deficient mice and BoTXC3-treated mice, as detected by paw-pressure test.
Figure 3: Absence of injury-induced dorsal root demyelination in LPA1-deficient or BoTXC3-treated mice.
Figure 4: Blockade of LPA- or injury-induced reduction of MBP and PMP22 expression in the dorsal root by BoTXC3.
Figure 5: Absence of injury-induced upregulation of PKCγ and Caα2δ1 expression in LPA1-deficient mice or BoTXC3-treated mice.

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Change history

  • 20 June 2004

    Replaced Figure 2c, corrected text

Notes

  1. NOTE: In the version of this article initially published online, on p. 715, at the beginning of the second column, the antisense oligonucleotide was identified incorrectly. The first complete sentence of the column should begin, “Moreover, preinjury injection with LPA1 AS-ODN...” In addition, the bottom curve in Figure 2c was labeled incorrectly. The label should read “Wild-type”. These errors have been corrected for the HTML and print versions of the article.

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Acknowledgements

We thank T. Kawashima, S. Kondo, M. Matsumoto and T. Suematsu for technical help and behavioral studies, and S. Kozaki for BoTXC3. This study was supported by Special Coordination Funds of the Science and Technology Agency of the Japanese Government and Grants-in-Aid from the Ministry of Education, Science, Culture and Sports of Japan (H.U.) and by the National Institute of Mental Health, USA (J.C., J.J.C.).

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Authors and Affiliations

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

    Makoto Inoue, Md Harunor Rashid, Ryousuke Fujita & Hiroshi Ueda

  2. Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N., Seattle, 98109-1024, Washington, USA

    James J A Contos

  3. Department of Molecular Biology, Helen L. Dorris Institute for Neurological and Psychiatric Disorders, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, 92037, California, USA

    Jerold Chun

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Correspondence to Hiroshi Ueda.

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Supplementary information

Supplementary Fig. 1 (PDF 314 kb)

Supplementary Fig. 2 (PDF 783 kb)

Supplementary Fig. 3

Schematic model showing role of LPA in development of neuropathic pain following peripheral nerve injury. (PDF 368 kb)

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Inoue, M., Rashid, M., Fujita, R. et al. Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling. Nat Med 10, 712–718 (2004). https://doi.org/10.1038/nm1060

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