A systems approach for discovering linoleic acid derivatives that potentially mediate 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.

Lipidomic profiling of targeted oxylipins with ultra-performance liquid chromatography-tandem mass spectrometry

“…Moreover, we found that these lipids cause pain and itch-related behaviors in rodent models. In addition, we used this assay to show that these novel lipids can be altered by changing the amounts of their precursor fatty acids in the diet [70]. It has also been successfully applied for the profiling of these lipid mediators in human psoriasis skin and blood and showed alterations of the targeted mediators by comparing to the healthy individuals [71].…”

Effect of the Enrichment of Corn Oil With alpha- or gamma-Tocopherol on Its In Vitro Digestion Studied by 1H NMR and SPME-GC/MS; Formation of Hydroperoxy-, Hydroxy-, Keto-Dienes and Keto-E-epoxy-E-Monoenes in the More alpha-Tocopherol Enriched Samples

“…The total bioaccessibility of these kinds of compounds ranges from 1.5 mmol (in the sample enriched with the lowest concentration of gamma-tocopherol) to 8.9 mmol (in the sample enriched with the highest level of alpha-tocopherol). Nevertheless, taking into account that these oxidized fatty acids are toxic, their absorption has direct detrimental effects on human health [6,[32][33][34]. By contrast, these compounds are not present in the digestates of the samples enriched with 2% and 5% of gamma-tocopherol, because in the digestion of these samples, no oxidation is produced.…”

“…Some evidence suggests that other reactions may also be possible, such as the Maillard reaction, esterification and oxidation [1][2][3]. Of these, oxidation could be a cause for concern, because it is known that certain compounds resulting from lipid oxidation are toxic and have been held responsible for several degenerative diseases [4][5][6].…”

Plasma oxylipins and unesterified precursor fatty acids are altered by DHA supplementation in pregnancy: Can they help predict risk of preterm birth?

“…T classes: (1) autacoids are labile signaling molecules that act locally and are rapidly inactivated or degraded; (2) pathway precursors are intermediates in the biosynthetic pathway leading to generation of more labile, bioactive autacoids; and (3) inactivation products are downstream metabolic derivatives that are often more stable than their autacoid precursors [4]. Oxylipins in these three categories are increasingly being measured in plasma collected in clinical studies to investigate biochemical mechanisms mediating disease [5][6][7][8], and to assess for pharmacodynamic biomarkers of nutrient-based and drugbased [9][10][11] interventions.…”