Association of the resolvin precursor 17-HDHA, but not D- or E- series resolvins, with heat pain sensitivity and osteoarthritis pain in humans

Ana M Valdes,Juliette Harris,Frances M K Williams,Tim D Spector,David A Barrett,Victoria Chapman,Ayrun Nessa,Abhishek Abhishek,Cristina Menni,Srinivasarao Ravipati,Sarah Metrustry,Michael Doherty

doi:10.1038/s41598-017-09516-3

Abstract

Resolvins are omega-3 fatty acid derived potent bioactive lipids that resolve inflammation and modulate transient receptor potential channels. Exogenous administration of the resolvin precursor 17-HDHA shows a strong analgesic effect in animal models of osteoarthritis and acute inflammatory pain, but has not been studied in humans. Our aim was to assess the role of 17-HDHA and resolvins in heat pain sensitivity and in osteoarthritis pain in humans. Resolvins D1, D2, D3, D5, E1 and 17-HDHA, were measured by liquid chromatography-mass spectrometry and tested for association with heat pain thresholds in 250 healthy volunteers who had undergone quantitative sensory testing. Resolvins D1, D2 and 17-HDHA were then tested in 62 individuals affected with knee osteoarthritis and 52 age matched controls and tested for association with knee pain. Circulating levels of docosahexaenoic acid (DHA) were also measured. Levels of 17-HDHA, but not those of the other 5 resolvins tested, were associated with increased heat pain thresholds (beta = 0.075; 95% CI 0.024, 0.126; p < 0.0046). 17-HDHA was associated with lower pain scores in OA patients (beta −0.41; 95% CI-0.69, −0.12; p < 0.005; adjusted for covariates) but not with radiographic osteoarthritis. The associations of 17-HDHA with heat pain sensitivity and osteoarthritis pain were independent of DHA levels.

Highlights

Osteoarthritis (OA) is the fastest growing cause of chronic pain worldwide and is the commonest form of arthritis[1]
In this study we show for the first time that 17-HDHA is associated with pain in humans, with thermal pain sensitivity and the intensity of chronic pain
We have shown that exogenous systemic administration of 17-hydroxy docosahexaenoic acid (17-HDHA abbreviated as 17-HDoHE) completely reversed established pain behaviour in the monosodium iodoacetate model of OA pain, an effect which lasted for 6 hours, and was sustained following repeated administration[17]

Summary

Introduction

Osteoarthritis (OA) is the fastest growing cause of chronic pain worldwide and is the commonest form of arthritis[1]. It has long been recognised that the amount of pain people with OA experience is variable and only weakly correlated to the extent of joint damage, but the molecular basis underlying variation in OA pain is poorly understood[2] It is well established pro-inflammatory agents are released into the joint and that synovitis is highly correlated to OA pain[3], various cytokines and pro-inflammatory mediators are released in damaged tissue and induce a cascade of events that lead to peripheral sensitization[4]. Resolvins are able to modulate N-Methyl-D-Aspartic acid (NMDA) receptors[11] (Fig. 1). Phosphorylation of these receptors has been associated with hyperalgesia, neuropathic pain, and reduced functionality of opioid receptors[12]. RvD1 has been shown to significantly attenuate arthritis severity and inflammation in a murine model of inflammatory arthritis but these protective actions are abolished in RvD1 receptor-deficient mice[14]

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