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.

Objective: To investigate the preliminary efficacy of a high n‐3 plus low n‐6 (H3‐L6) dietary intervention in improving mood stability in Bipolar Disorder (BD) when compared to dietary intervention with usual U.S. levels of n‐6 and n‐3 polyunsaturated fatty acid (PUFA) intakes (control diet, CD).Methods: This 2‐arm, parallel‐group, randomized, modified double‐blind, controlled 48‐week study of 12‐week intensive diet intervention in subjects with BD was conducted at a single suburban‐rural site in the mid‐Atlantic region. Participants with DSM‐IV TR BD I or II with hypomanic or depressive symptoms were randomized, stratified on gender (N = 82). The intervention included the provision of group‐specific study foods and dietary counseling. Variability of mood symptoms was measured by a twice‐daily, 12‐week ecological momentary analysis (EMA) paradigm, and group differences were analyzed using multilevel models. Circulating n‐3 and n‐6 fatty acids were measured at baseline and after 4, 8, and 12 weeks of diet exposure.Results: All 82 randomized participants were included in biochemical analyses. Seventy participants completed at least 2 EMA surveys and were included in primary EMA analyses. Variability in mood, energy, irritability, and pain as measured using EMA was reduced in the H3‐L6 group compared to the CD group. No significant differences in mean ratings of mood symptoms, or any other symptom measures, were detected. The dietary intervention effect on target PUFAs significantly differed by the group over time.Conclusions: A dietary intervention adjunctive to usual care showed preliminary efficacy in improving variability in mood symptoms in participants with BD.Trial Registration: ClinicalTrials.Gov NCT02272010.

Postoperative pain and delayed healing in surgical wounds, which require complex management strategies have understudied complicated mechanisms. Here we investigated temporal changes in behavior, tissue structure, and transcriptomic profiles in a rat model of a surgical incision, using hyperalgesic behavioral tests, histological analyses, and next‐generation RNA sequencing, respectively. The most rapidly (1 hour) expressed genes were the chemokines, Cxcl1 and Cxcl2 . Consequently, infiltrating leukocytes were abundantly observed starting at 6 and peaking at 24 hours after incising which was supported by histological analysis and appearance of the neutrophil markers, S100a8 and S100a9 . At this time, hyperalgesia was at a peak and overall transcriptional activity was most highly activated. At the 1‐day timepoint, Nppb , coding for natriuretic peptide precursor B, was the most strongly upregulated gene and was localized by in situ hybridization to the epidermal keratinocytes at the margins of the incision. Nppb was basically unaffected in a peripheral inflammation model transcriptomic dataset. At the late phase of wound healing, five secreted, incision‐specific peptidases, Mmp2 , Aebp1 , Mmp23 , Adamts7 , and Adamtsl1 , showed increased expression, supporting the idea of a sustained tissue remodeling process. Transcripts that are specifically upregulated at each timepoint in the incision model may be potential candidates for either biomarkers or therapeutic targets for wound pain and wound healing. This study incorporates the examination of longitudinal temporal molecular responses, corresponding anatomical localization, and hyperalgesic behavioral alterations in the surgical incision model that together provide important and novel foundational knowledge to understand mechanisms of wound pain and wound healing.