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A systems approach for discovering linoleic acid derivatives that potentially mediate pain and itch

2017; American Association for the Advancement of Science; Volume: 10; Issue: 493 Linguagem: Inglês

10.1126/scisignal.aal5241

1937-9145

Christopher E. Ramsden, Anthony F. Domenichiello, Zhi‐Xin Yuan, Matthew R. Sapio, Gregory S. Keyes, Santosh K. Mishra, Jacklyn R. Gross, Sharon F. Majchrzak‐Hong, Daisy Zamora, Mark S. Horowitz, John M. Davis, Alexander V. Sorokin, Amit Dey, Danielle M. LaPaglia, Joshua J. Wheeler, Michael R. Vasko, Nehal N. Mehta, Andrew J. Mannes, Michael J. Iadarola,

Adipose Tissue and Metabolism

Chronic pain and itch are common hypersensitivity syndromes that are affected by endogenous mediators. We applied a systems-based, translational approach to predict, discover, and characterize mediators of pain and itch that are regulated by diet and inflammation. Profiling of tissue-specific precursor abundance and biosynthetic gene expression predicted that inflamed skin would be abundant in four previously unknown 11-hydroxy-epoxy- or 11-keto-epoxy-octadecenoate linoleic acid derivatives and four previously identified 9- or 13-hydroxy-epoxy- or 9- or 13-keto-epoxy-octadecenoate linoleic acid derivatives. All of these mediators were confirmed to be abundant in rat and human skin by mass spectrometry. However, only the two 11-hydroxy-epoxy-octadecenoates sensitized rat dorsal root ganglion neurons to release more calcitonin gene-related peptide (CGRP), which is involved in pain transmission, in response to low pH (which mimics an inflammatory state) or capsaicin (which activates ion channels involved in nociception). The two 11-hydroxy-epoxy-octadecenoates share a 3-hydroxy-