Nature Medicine10, 712 - 718 (2004)
Published online: 13 June 2004; Corrected online: 20 2004 | doi:10.1038/nm1060
There is an Erratum (July 2004) associated with this document.
Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling
Makoto Inoue1, Md Harunor Rashid1, Ryousuke Fujita1, James J A Contos2, Jerold Chun3
& 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
Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N., Seattle, Washington 98109-1024, USA.
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, California 92037, USA.
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 -isoform within the spinal cord dorsal horn and the 21 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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-isoform within the spinal cord dorsal horn and the 
2
1 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.
