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

doi:10.3389/fphar.2018.00412

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.

Highlights

Nerve injury-induced neuropathic pain due to diabetic neuropathy, viral infection, and chemotherapy is a major health problem worldwide (Woolf and Mannion, 1999; Dworkin et al, 2003; Campbell and Meyer, 2006; Kehlet et al, 2006)
The acetone test revealed that sham surgery caused a slight increase in cold response scores for 5 days (P > 0.05, one-way ANOVA, Figure 1C). These results indicate that sham surgery produces transient mechanical and cold allodynia
This study measured plasma concentrations of specialized pro-resolving mediators (SPMs) [such as Resolvin D2 (RvD2) and the immediate precursors of resolvins and neuroprotectins; 17-hydroxy-docosahexaenoic (17-HDHA) and 18-hydroxy-eicosapentaenoic acid (18-HEPE)] and confirmed that SPMs are converted from dietary omega-3 supplements (Ramsden et al, 2013; Van De Ven and Ji, 2013), suggesting that

Summary

Introduction

Nerve injury-induced neuropathic pain due to diabetic neuropathy, viral infection, and chemotherapy is a major health problem worldwide (Woolf and Mannion, 1999; Dworkin et al, 2003; Campbell and Meyer, 2006; Kehlet et al, 2006). Common major surgeries frequently lead to the development of chronic post-operative pain (POP; Kehlet et al, 2006). Fracture associated POP (fPOP) is related to nerve injury, as reflected by a robust induction of the transcription factor ATF3 in sensory neurons, as well as neuroinflammation in the peripheral and central nervous system (Li et al, 2015; Zhang et al, 2016). Dysregulation of glial cells (gliopathy) contributes to the pathogenesis of pain in part by promoting neuroinflammation (McMahon and Malcangio, 2009; Ji et al, 2013, 2018; Tsuda, 2017)

Methods

Results

Discussion

Conclusion