Research ArticleNOCICEPTION

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

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Sci. Signal.  22 Aug 2017:
Vol. 10, Issue 493, eaal5241
DOI: 10.1126/scisignal.aal5241

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Deriving itch and pain from a fatty acid

Linoleic acid is a polyunsaturated ω−6 fatty acid that is consumed in high amounts in a typical Western diet and whose derivatives are associated with chronic inflammation and pain. Ramsden et al. identified several derivatives of linoleic acid in inflamed psoriatic lesions. One of these derivatives [9-keto-12,13-trans-epoxy-(10E)-octadecenoate] was much more abundant in itchy psoriatic lesions than in non-itchy psoriatic lesions or normal skin, and it induced scratching when injected into mice. Injection of another linoleic acid derivative [11-hydroxy-12,13-trans-epoxy-(9Z)-octadecenoate] caused rats to become more sensitive to thermal pain. Furthermore, chronic headache sufferers reported shorter headaches and more headache-free days when they reduced their dietary intake of linoleic acid, which was associated with decreased plasma concentrations of 11-hydroxy-12,13-trans-epoxy-(9Z)-octadecenoate. Identifying the receptor for these linoleic acid derivatives could reveal a potential pharmacological target to reduce pain and itch.

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-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-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 to manage 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.

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