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

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

Whole-body DHA synthesis-secretion kinetics from plasma eicosapentaenoic acid and alpha-linolenic acid in the free-living rat

AbstractWhole body docosahexaenoic acid (DHA, 22:6n-3) synthesis from α-linolenic acid (ALA, 18:3n-3) is considered to be very low, however, the daily synthesis-secretion of DHA may be sufficient to supply the adult brain. The current study aims to assess whether whole body DHA synthesis-secretion kinetics are different when comparing plasma ALA versus eicosapentaenoic acid (EPA, 20:5n-3) as the precursor. Male Long Evans rats (n=6) were fed a 2% ALA in total fat diet for eight weeks, followed by surgery to implant a catheter into each of the jugular vein and carotid artery and 3h of steady-state infusion with a known amount of 2H-ALA and 13C-eicosapentaenoic acid (EPA, 20:5n3). Blood samples were collected at thirty-minute intervals and plasma enrichment of 2H- and 13C EPA, n−3 docosapentaenoic acid (DPAn-3, 22:5n-3) and DHA were determined for assessment of synthesis-secretion kinetic parameters. Results indicate a 13-fold higher synthesis-secretion coefficient for DHA from EPA as compared to ALA. However, after correcting for the 6.6 fold higher endogenous plasma ALA concentration, no significant differences in daily synthesis-secretion (nmol/day) of DHA (97.6±28.2 and 172±62), DPAn-3 (853±279 and 1139±484) or EPA (1587±592 and 1628±366) were observed from plasma unesterified ALA and EPA sources, respectively. These results suggest that typical diets which are significantly higher in ALA compared to EPA yield similar daily DHA synthesis-secretion despite a significantly higher synthesis-secretion coefficient from EPA

Endogenous Derivatives of Linoleic Acid and their Stable Analogs Are Potential Pain Mediators.

Psoriasis is characterized by intense pruritus, with a subset of individuals with psoriasis experiencing thermal hypersensitivity. However, the pathophysiology of thermal hypersensitivity in psoriasis and other skin conditions remains enigmatic. Linoleic acid is an omega-6 fatty acid that is concentrated in the skin, and oxidation of linoleic acid into metabolites with multiple hydroxyl and epoxide functional groups has been shown to play a role in skin barrier function. Previously, we identified several linoleic acid‒derived mediators that were more concentrated in psoriatic lesions, but the role of these lipids in psoriasis remains unknown. In this study, we report that two such compounds-9,10-epoxy-13-hydroxy-octadecenoate and 9,10,13-trihydroxy-octadecenoate-are present as free fatty acids and induce nociceptive behavior in mice but not in rats. By chemically stabilizing 9,10-epoxy-13-hydroxy-octadecenoate and 9,10,13-trihydroxy-octadecenoate through the addition of methyl groups, we observed pain and hypersensitization in mice. The nociceptive responses suggest an involvement of the TRPA1 channel, whereas hypersensitive responses induced by these mediators may require both TRPA1 and TRPV1 channels. Furthermore, we showed that 9,10,13-trihydroxy-octadecenoate‒induced calcium transients in sensory neurons are mediated through the Gβγ subunit of an unidentified G-protein coupled receptor (GPCR). Overall, mechanistic insights from this study will guide the development of potential therapeutic targets for the treatment of pain and hypersensitivity