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      An LPA species (18:1 LPA) plays key roles in the self-amplification of spinal LPA production in the peripheral neuropathic pain model

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          Abstract

          Background

          We previously reported that nerve injury-induced neuropathic pain is initiated by newly produced lysophosphatidic acid (LPA).

          Results

          In this study, we developed a quantitative mass spectrometry for detecting LPA species by using Phos-tag. Following nerve injury, the levels of 18:1, 16:0 and 18:0 LPA in the spinal dorsal horn significantly increased at 3 h and declined at 6 h. Among them, 18:1 LPA level was the most abundant. In the same preparation, there were significant elevations in the activities of cytosolic phospholipase A 2 (cPLA 2) and calcium-independent phospholipase A 2 (iPLA 2), key enzymes for LPA synthesis, at 1 h, while there was no significant change in phospholipase A 1 activity. Pharmacological studies revealed that NMDA and neurokinin 1 receptors, cPLA 2, iPLA 2 and microglial activation, as well as LPA 1 and LPA 3 receptors were all involved in the nerve injury-induced LPA production, and underlying cPLA 2 and iPLA 2 activations. In the cells expressing LPA 1 or LPA 3 receptor, the receptor-mediated calcium mobilization was most potent with 18:1 LPA, compared with 16:0 or 18:0 LPA. Moreover, the intrathecal injection of 18:1 LPA, but not 16:0 or 18:0 LPA, caused a spinal LPA production and neuropathic pain-like behavior.

          Conclusion

          These results suggest that 18:1 LPA is the predominant ligand responsible for LPA 1 and LPA 3 receptors-mediated amplification of LPA production through microglial activation.

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          Most cited references44

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          A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia.

          A method to measure cutaneous hyperalgesia to thermal stimulation in unrestrained animals is described. The testing paradigm uses an automated detection of the behavioral end-point; repeated testing does not contribute to the development of the observed hyperalgesia. Carrageenan-induced inflammation resulted in significantly shorter paw withdrawal latencies as compared to saline-treated paws and these latency changes corresponded to a decreased thermal nociceptive threshold. Both the thermal method and the Randall-Selitto mechanical method detected dose-related hyperalgesia and its blockade by either morphine or indomethacin. However, the thermal method showed greater bioassay sensitivity and allowed for the measurement of other behavioral parameters in addition to the nociceptive threshold.
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            The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak.

            Aberrant wound-healing responses to injury have been implicated in the development of pulmonary fibrosis, but the mediators directing these pathologic responses have yet to be fully identified. We show that lysophosphatidic acid levels increase in bronchoalveolar lavage fluid following lung injury in the bleomycin model of pulmonary fibrosis, and that mice lacking one of its receptors, LPA1, are markedly protected from fibrosis and mortality in this model. The absence of LPA1 led to reduced fibroblast recruitment and vascular leak, two responses that may be excessive when injury leads to fibrosis rather than to repair, whereas leukocyte recruitment was preserved during the first week after injury. In persons with idiopathic pulmonary fibrosis, lysophosphatidic acid levels in bronchoalveolar lavage fluid were also increased, and inhibition of LPA1 markedly reduced fibroblast responses to the chemotactic activity of this fluid. LPA1 therefore represents a new therapeutic target for diseases in which aberrant responses to injury contribute to fibrosis, such as idiopathic pulmonary fibrosis.
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              Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling.

              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 LPA(1) 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 gamma-isoform within the spinal cord dorsal horn and the alpha(2)delta(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 (LPA(1), 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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                Author and article information

                Contributors
                Journal
                Mol Pain
                Mol Pain
                Molecular Pain
                BioMed Central
                1744-8069
                2013
                17 June 2013
                : 9
                : 29
                Affiliations
                [1 ]Department 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, Dorris Neuroscience Center, The Scripps Research Institute, 10550 North Torrey Pines Road, ICND118, La Jolla, CA 92037, USA
                Article
                1744-8069-9-29
                10.1186/1744-8069-9-29
                3691926
                23773289
                16a3d997-8d26-4d8e-9099-1c122d50b296
                Copyright © 2013 Ma et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 15 April 2013
                : 12 June 2013
                Categories
                Research

                Molecular medicine
                lysophosphatidic acid,neuropathic pain,maldi-tofms,phos-tag,cytosolic phospholipase a2,neuron

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