Metabolomics implicates altered sphingolipids in chronic pain of neuropathic origin

Abstract

Neuropathic pain is a debilitating condition for which the development of effective treatments has been limited by an incomplete understanding of its chemical basis. We show by using untargeted metabolomics that sphingomyelin-ceramide metabolism is altered in the dorsal horn of rats with neuropathic pain and that the upregulated, endogenous metabolite N,N-dimethylsphingosine induces mechanical hypersensitivity in vivo. These results demonstrate the utility of metabolomics to implicate unexplored biochemical pathways in disease.

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Figure 1: Untargeted metabolomics identifies the dysregulation of sphingomyelin-ceramide metabolism in the ipsilateral dorsal horn during chronic neuropathic pain.
Figure 2: DMS elicits neuropathic pain behavior and cytokine release.

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Acknowledgements

This work was supported by the US National Institutes of Health (NIH) R24 EY017540-04 (G.S.), P30 MH062261 (M.M., G.S.) and P01 DA026146-02 (G.S.) in addition to RR025774 (M.M.); NIH–National Institute of Aging L30 AG0 038036 (G.J.P.); and NIH–National Institute of Neurological Disorders and Stroke F32NS068015 and T32 NSO41219 (L.P.S.). We also acknowledge financial support from the US Department of Energy FG02-07ER64325 and DE-AC0205CH11231).

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G.J.P. and O.Y. contributed equally to this work. G.J.P., L.P.S. and J.C. performed work on rats. G.J.P., O.Y. and L.P.S. performed analytical experiments. G.J.P., O.Y., L.P.S., J.-P.C., R.T., M.M. and G.S. contributed to experimental design, performed data analysis and wrote the manuscript.

Corresponding authors

Correspondence to Marianne Manchester or Gary Siuzdak.

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The authors declare no competing financial interests.

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Patti, G., Yanes, O., Shriver, L. et al. Metabolomics implicates altered sphingolipids in chronic pain of neuropathic origin. Nat Chem Biol 8, 232–234 (2012). https://doi.org/10.1038/nchembio.767

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