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    Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation

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    Grenald-etal.-2017.pdf
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    Final Accepted Manuscript
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    Author
    Grenald, Shaness A
    Doyle, Timothy M
    Zhang, Hong
    Slosky, Lauren M
    Chen, Zhoumou
    Largent-Milnes, Tally M
    Spiegel, Sarah
    Vanderah, Todd W
    Salvemini, Daniela
    Affiliation
    Univ Arizona, Dept Pharmacol
    Issue Date
    2017-09-01
    Keywords
    S1PR1 antagonists
    FTY720
    TASP0277308
    IL-10
    
    Metadata
    Show full item record
    Publisher
    LIPPINCOTT WILLIAMS & WILKINS
    Citation
    Grenald, S. A., Doyle, T. M., Zhang, H., Slosky, L. M., Chen, Z., Largent-Milnes, T. M., ... & Salvemini, D. (2017). Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation. Pain, 158(9), 1733.
    Journal
    PAIN
    Rights
    © 2017 International Association for the Study of Pain.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    Metastatic bone pain is the single most common form of cancer pain and persists as a result of peripheral and central inflammatory, as well as neuropathic mechanisms. Here, we provide the first characterization of sphingolipid metabolism alterations in the spinal cord occurring during cancer-induced bone pain (CIBP). Following femoral arthrotomy and syngenic tumor implantation in mice, ceramides decreased with corresponding increases in sphingosine and the bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P). Intriguingly, de novo sphingolipid biosynthesis was increased as shown by the elevations of dihydro-ceramides and dihydro-S1P. We next identified the S1P receptor subtype 1 (S1PR1) as a novel target for therapeutic intervention. Intrathecal or systemic administration of the competitive and functional S1PR1 antagonists, TASP0277308 and FTY720/Fingolimod, respectively, attenuated cancer-induced spontaneous flinching and guarding. Inhibiting CIBP by systemic delivery of FTY720 did not result in antinociceptive tolerance over 7 days. FTY720 administration enhanced IL-10 in the lumbar ipsilateral spinal cord of CIBP animals and intrathecal injection of an IL-10 neutralizing antibody mitigated the ability of systemic FTY720 to reverse CIBP. FTY720 treatment was not associated with alterations in bone metabolism in vivo. Studies here identify a novel mechanism to inhibit bone cancer pain by blocking the actions of the bioactive metabolites S1P and dihydro-S1P in lumbar spinal cord induced by bone cancer and support potential fast-track clinical application of the FDA-approved drug, FTY720, as a therapeutic avenue for CIBP.
    Note
    12 month embargo; published online: 31 May 2017
    ISSN
    1872-6623
    PubMed ID
    28570482
    DOI
    10.1097/j.pain.0000000000000965
    Version
    Final accepted manuscript
    Sponsors
    NIH-NCI Cancer Center [P30 CA016059]
    Additional Links
    https://journals.lww.com/pain/fulltext/2017/09000/Targeting_the_S1P_S1PR1_axis_mitigates.13.aspx
    ae974a485f413a2113503eed53cd6c53
    10.1097/j.pain.0000000000000965
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