Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation
AuthorGrenald, Shaness A
Doyle, Timothy M
Slosky, Lauren M
Largent-Milnes, Tally M
Vanderah, Todd W
AffiliationUniv Arizona, Dept Pharmacol
MetadataShow full item record
PublisherLIPPINCOTT WILLIAMS & WILKINS
CitationGrenald, 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.
Rights© 2017 International Association for the Study of Pain
Collection InformationThis 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 email@example.com.
AbstractMetastatic 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.
Note12 month embargo; published online: 31 May 2017
VersionFinal accepted manuscript
SponsorsNIH-NCI Cancer Center [P30 CA016059]
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