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. 2013 Dec 9;8(12):e81228.
doi: 10.1371/journal.pone.0081228. eCollection 2013.

Synthesis of Lipid Mediators During UVB-induced Inflammatory Hyperalgesia in Rats and Mice

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Free PMC article

Synthesis of Lipid Mediators During UVB-induced Inflammatory Hyperalgesia in Rats and Mice

Marco Sisignano et al. PLoS One. .
Free PMC article

Abstract

Peripheral sensitization during inflammatory pain is mediated by a variety of endogenous proalgesic mediators including a number of oxidized lipids, some of which serve endogenous modulators of sensory TRP-channels. These lipids are eicosanoids of the arachidonic acid and linoleic acid pathway, as well as lysophophatidic acids (LPAs). However, their regulation pattern during inflammatory pain and their contribution to peripheral sensitization is still unclear. Here, we used the UVB-model for inflammatory pain to investigate alterations of lipid concentrations at the site of inflammation, the dorsal root ganglia (DRGs) as well as the spinal dorsal horn and quantified 21 lipid species from five different lipid families at the peak of inflammation 48 hours post irradiation. We found that known proinflammatory lipids as well as lipids with unknown roles in inflammatory pain to be strongly increased in the skin, whereas surprisingly little changes of lipid levels were seen in DRGs or the dorsal horn. Importantly, although there are profound differences between the number of cytochrome (CYP) genes between mice and rats, CYP-derived lipids were regulated similarly in both species. Since TRPV1 agonists such as LPA 18∶1, 9- and 13-HODE, 5- and 12-HETE were elevated in the skin, they may contribute to thermal hyperalgesia and mechanical allodynia during UVB-induced inflammatory pain. These results may explain why some studies show relatively weak analgesic effects of cyclooxygenase inhibitors in UVB-induced skin inflammation, as they do not inhibit synthesis of other proalgesic lipids such as LPA 18∶1, 9-and 13-HODE and HETEs.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Mechanical allodynia after UV-B-irradiation in BL/6N-mice.
Mice were irradiated at the plantar side of the hind paw with the indicated UV-B-doses. Mechanical thresholds were measured up to seven days post irradiation with the dynamic plantar test; bl: baseline. Data represents the average ± SEM from 10 animals per group; **p<0.01, ***p<0.001, two way repeated-measures ANOVA with Bonferroni post-hoc test.
Figure 2
Figure 2. Prostanoid concentrations in skin, DRG and spinal dorsal horn samples from irradiated mice 48 h post irradiation.
Concentrations of prostanoids from isolated skin (A), L4–L6-DRGs (B) and spinal dorsal horn tissue (C) of mice comparing untreated (black bars) versus irradiated skin (grey bars); 6-k-PGF1α: 6-keto-Prostaglandin F1α. Data represent mean ± SEM from six mice per group; *p<0.05, **p<0.01, ***p<0.001, student’s t-test.
Figure 3
Figure 3. Concentrations of HETEs, LPAs and HODEs in skin, L4–L6-DRGs and spinal dorsal horn samples from irradiated mice.
Shown are the concentrations of LTB4, 5-, 12-, 15- and 20-HETE from isolated skin (A), L4–L6-DRGs (B) and the corresponding section of the dorsal horn (C)., n.d, not detectable. (D–F) Levels of LPAs 16∶0, 18∶0, 18∶1 and 18∶2 in skin (D), L4–L6-DRGs (E) and the spinal dorsal horn (F) of irradiated versus untreated mice. (G–I) Shown are the concentrations of 9- and 13-HODE from skin (G), L4–L6-DRGs (H) and the dorsal horn of the spinal cord (I). Data represent mean ± SEM from six mice per group, *p<0.05, **p<0.01, student’s t-test.
Figure 4
Figure 4. Mechanical thresholds of C57/Bl6 mice after injection of LTB4, 5-HETE, LPA 16∶0 or LPA 18∶0.
Shown are paw withdrawal thresholds of wild type BL6 mice after intraplantar injection of LTB4 (10 µl of a 6 µM solution, A), 5-HETE (10 µl of a 6 µM solution B), LPA 16∶0 and LPA 18∶0 (both 10 µl of a 10 µM solution, C) and the corresponding vehicle (0.4% Ethanol (v/v) for LTB4 and 5-HETE, 1% DMSO (v/v) for LPA 16∶0 and LPA 18∶0). Mechanical thresholds were monitored until 6 h post injection (LTB4 and 5-HETE) or until 30 h post injection (LPA 16∶0 and LPA 18∶0). Data represent mean ± SEM from 6–8 mice per group (LTB4 and 5-HETE) or 7–11 mice per group (LPA 16∶0 and LPA 18∶0); *p<0.05, **p<0.01, ***p<0.001 two way repeated-measures ANOVA with Bonferroni post-hoc test. Structures were obtained from lipidmaps.org.
Figure 5
Figure 5. Comparison of epoxylipid-levels in skin tissue from irradiated mice and rats.
Shown are the concentrations of 9,10- and 12,13-EpOME, and their metabolites 9,10–12,13-DiHOME, as well as 14,15-EET in skin from irradiated mice (A) and rats (B). Data represent mean ± SEM from five rats and six mice per group; *p<0.05, **p<0.01, ***p<0.001, student’s t-test.

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