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

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

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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-epoxyor 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 lowpH (which mimics an inflammatory state) or capsaicin (which activates ion channels involved in nociception). The two 11-hydroxy-epoxy-octadecenoates share a 3-hydroxy-Z-pentenyl-E-epoxide moiety, thus suggesting that this substructure could mediate nociceptor sensitization. In rats, intradermal hind paw injection of 11-hydroxy-12,13-trans-epoxy-(9Z)-octadecenoate elicited C-fiber-mediated sensitivity to thermal pain. In a randomized trial testing adjunctive strategies tomanage refractory chronic headaches, reducing the dietary intake of linoleic acid was associated with decreases in plasma 11-hydroxy-12,13-trans-epoxy-(9Z)-octadecenoate, which correlated with clinical pain reduction. Human psoriatic skin had 30-fold higher 9-keto-12,13-trans-epoxy- (10E)-octadecenoate compared to control skin, and intradermal injection of this compound induced itch-related scratching behavior in mice. Collectively, these findings define a family of endogenous mediators with potential roles in pain and itch.

Original languageEnglish (US)
Article number5241
JournalScience Signaling
Volume10
Issue number493
StatePublished - Aug 22 2017

Fingerprint

Linoleic Acid
Systems Analysis
Skin
Derivatives
Rats
Pain
Calcitonin Gene-Related Peptide
Capsaicin
Epoxy Compounds
Nutrition
Intradermal Injections
Unmyelinated Nerve Fibers
Ion Channels
Nociceptors
Headache Disorders
Gene expression
Nociception
Refractory materials
Neurons
Mass spectrometry

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Ramsden, C. E., Domenichiello, A. F., Yuan, Z. X., Sapio, M. R., Keyes, G. S., Mishra, S. K., ... Iadarola, M. J. (2017). A systems approach for discovering linoleic acid derivatives that potentially mediate pain and itch. Science Signaling, 10(493), [5241].

A systems approach for discovering linoleic acid derivatives that potentially mediate pain and itch. / Ramsden, Christopher E.; Domenichiello, Anthony F.; Yuan, Zhi Xin; Sapio, Matthew R.; Keyes, Gregory S.; Mishra, Santosh K.; Gross, Jacklyn R.; Majchrzak-Hong, Sharo; Zamora, Daisy; Horowitz, Mark S.; Davis, John M.; Sorokin, Alexander V.; Dey, Amit; LaPaglia, Danielle M.; Wheeler, Joshua J.; Vasko, Michael; Mehta, Nehal N.; Mannes, Andrew J.; Iadarola, Michael J.

In: Science Signaling, Vol. 10, No. 493, 5241, 22.08.2017.

Research output: Contribution to journalArticle

Ramsden, CE, Domenichiello, AF, Yuan, ZX, Sapio, MR, Keyes, GS, Mishra, SK, Gross, JR, Majchrzak-Hong, S, Zamora, D, Horowitz, MS, Davis, JM, Sorokin, AV, Dey, A, LaPaglia, DM, Wheeler, JJ, Vasko, M, Mehta, NN, Mannes, AJ & Iadarola, MJ 2017, 'A systems approach for discovering linoleic acid derivatives that potentially mediate pain and itch', Science Signaling, vol. 10, no. 493, 5241.
Ramsden CE, Domenichiello AF, Yuan ZX, Sapio MR, Keyes GS, Mishra SK et al. A systems approach for discovering linoleic acid derivatives that potentially mediate pain and itch. Science Signaling. 2017 Aug 22;10(493). 5241.
Ramsden, Christopher E. ; Domenichiello, Anthony F. ; Yuan, Zhi Xin ; Sapio, Matthew R. ; Keyes, Gregory S. ; Mishra, Santosh K. ; Gross, Jacklyn R. ; Majchrzak-Hong, Sharo ; Zamora, Daisy ; Horowitz, Mark S. ; Davis, John M. ; Sorokin, Alexander V. ; Dey, Amit ; LaPaglia, Danielle M. ; Wheeler, Joshua J. ; Vasko, Michael ; Mehta, Nehal N. ; Mannes, Andrew J. ; Iadarola, Michael J. / A systems approach for discovering linoleic acid derivatives that potentially mediate pain and itch. In: Science Signaling. 2017 ; Vol. 10, No. 493.
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