Distinct Analgesic Actions of DHA and DHA-Derived Specialized Pro-Resolving Mediators on Post-operative Pain After Bone Fracture in Mice

Linlin Zhang, Niccolò Terrando, Zhen-Zhong Xu, Sangsu Bang, Sven-Eric Jordt, William Maixner, Charles N Serhan, Ru-Rong Ji, Linlin Zhang, Niccolò Terrando, Zhen-Zhong Xu, Sangsu Bang, Sven-Eric Jordt, William Maixner, Charles N Serhan, Ru-Rong Ji

Abstract

Mechanisms of pain resolution are largely unclear. Increasing evidence suggests that specialized pro-resolving mediators (SPMs), derived from fish oil docosahexaenoic acid (DHA), promote the resolution of acute inflammation and potently inhibit inflammatory and neuropathic pain. In this study, we examined the analgesic impact of DHA and DHA-derived SPMs in a mouse model of post-operative pain induced by tibial bone fracture (fPOP). Intravenous perioperative treatment with DHA (500 μg), resolvin D1 (RvD1, 500 ng) and maresin 1 (MaR1, 500 ng), 10 min and 24 h after the surgery, delayed the development of fPOP (mechanical allodynia and cold allodynia). In contrast, post-operative intrathecal (IT) administration of DHA (500 μg) 2 weeks after the surgery had no effects on established mechanical and cold allodynia. However, by direct comparison, IT post-operative treatment (500 ng) with neuroprotectin D1 (NPD1), MaR1, and D-resolvins, RvD1 and RvD5, but not RvD3 and RvD4, effectively reduced mechanical and cold allodynia. ELISA analysis showed that perioperative DHA treatment increased RvD1 levels in serum and spinal cord samples after bone fracture. Interestingly, sham surgery resulted in transient allodynia and increased RvD1 levels, suggesting a correlation of enhanced SPM levels with acute pain resolution after sham surgery. Our findings suggest that (1) perioperative treatment with DHA is effective in preventing and delaying the development of fPOP and (2) post-treatment with some SPMs can attenuate established fPOP. Our data also indicate that orthopedic surgery impairs SPM production. Thus, DHA and DHA-derived SPMs should be differentially supplemented for treating fPOP and improving recovery.

Keywords: DHA (docosahexaenoic acid); SPMs (specialized pro-resolving mediators); fPOP (post-operative pain after bone fracture); omega-3 poly unsaturated fatty acids; orthopedic surgery; post-surgical pain; spinal cord.

Figures

FIGURE 1
FIGURE 1
Effects of sham surgery, bone fracture, and perioperative DHA treatment on the development of fPOP. Development of mechanical allodynia, assessed by paw withdrawal threshold (A) and paw withdrawal frequency to 0.16 g filament (B) in von Frey test, after sham surgery, tibial bone fracture, and perioperative treatment of DHA (0.5 mg, 100 μl, i.v.), given 10 min and 24 h after bone fracture surgery (indicated by blue arrows). (C) Development of cold allodynia, assessed by cold response scoring in the acetone test, after sham surgery, tibial bone fracture, and the perioperative DHA treatment after bone fracture surgery (indicated by blue arrows). $P < 0.05, one-way ANOVA in Sham group vs. baseline; ∗P < 0.05 vs. Sham surgery; #P < 0.05, fracture vs. fracture + DHA; two-way ANOVA followed by Bonferroni test, n = 6–7 mice/group. Data are presented as mean ± SEM.
FIGURE 2
FIGURE 2
Perioperative DHA treatment increases RvD1 levels in serum and spinal cord. (A) RvD1 standard curve produced by the Cayman Chemical ELISA assay, demonstrating reliable measurements within the specified concentration range. RvD1 levels in serum samples (B), brain samples (C), and spinal cord samples (D) of naïve mice and mice after sham surgery or bone fracture with vehicle and DHA treatment (the same as described in Figure 1). Samples were collected at post-operative day 5 (POD 5). Note that RvD1 levels are elevated after sham surgery and in serum and spinal cord samples after the DHA treatment. ∗P < 0.05, one-way ANOVA; n = 3–10 mice per group. Data are presented as mean ± SEM.
FIGURE 3
FIGURE 3
Perioperative treatment of RvD1 and MaR1 attenuates fPOP. Impact of perioperative treatment of RvD1 and MaR1 (500 ng, 100 μl, i.v.), given 10 min and 24 h after bone fracture surgery (indicated by blue arrows), on mechanical allodynia, assessed by paw withdrawal threshold (A) and paw withdrawal frequency (B) in the von Frey test, as well as on cold allodynia, assessed by cold response scoring in the acetone test (C). ∗P < 0.05 vs. vehicle (5% ethanol), two-way ANOVA followed by Bonferroni test, n = 5 mice/group. Data are presented as mean ± SEM.
FIGURE 4
FIGURE 4
Distinct actions of post-treatment of DHAand DHA-derived SPMs on fPOP. Impact of post-surgical treatment with DHA (500 μg, i.t.) or DHA-derived SPMs RvD1, MaR1, NPD1, and RvD5 (500 ng, 10 μl, i.t.), given 2 weeks after bone fracture surgery (indicated by blue arrows) on mechanical allodynia, assessed by measurements of paw withdrawal threshold (A) and paw withdrawal frequency (B) in the von Frey test, as well as of cold allodynia, assessed by cold response scoring in the acetone test (C). Note that post-treatment of DHA has no effects on fPOP. ∗P < 0.05 vs. vehicle (10% ethanol), two-way ANOVA followed by Bonferroni test, n = 5–7 mice/group. Data are presented as mean ± SEM.
FIGURE 5
FIGURE 5
Area under curve (AUC) comparison of distinct post-treatment effects of DHA and DHA-derived SPMs on fPOP. (A–C) AUC showing the effects of post-surgical IT treatment of DHA (500 μg, 10 μl) and NPD1, MaR1, RvD1, RvD3, RvD4, and RvD5 (500 ng, 10 μl), given 2 weeks after bone fracture surgery on mechanical and cold allodynia. AUC data were collected at 1–5 h after the drug injection. ∗P < 0.05 vs. vehicle (10% ethanol), two-way ANOVA followed by Bonferroni test, n = 5–7 mice/group. Data are presented as mean ± SEM.

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