Targeting the D Series Resolvin Receptor System for the Treatment of Osteoarthritis Pain

Abstract

ObjectivePain is a major symptom of osteoarthritis (OA); currently available analgesics either do not provide adequate pain relief or are associated with serious side effects. The aim of this study was to investigate the therapeutic potential of targeting the resolvin receptor system to modify OA pain and pathology.MethodsGene expression of 2 resolvin receptors (ALX and ChemR23) was quantified in synovium and medial tibial plateau specimens obtained from patients with OA at the time of joint replacement surgery. Two models of OA joint pain were used for the mechanistic studies. Gene expression in the joint and central nervous system was quantified. The effects of exogenous administration of the D series resolvin precursor 17(R)‐hydroxy‐docosahexaenoic acid (17[R]‐HDoHE) on pain behavior, joint pathology, spinal microglia, and astroglyosis were quantified. Plasma levels of relevant lipids, resolvin D2, 17(R)‐HDoHE, and arachidonic acid, were determined in rats, using liquid chromatography tandem mass spectrometry.ResultsThere was a positive correlation between resolvin receptor and interleukin‐6 (IL‐6) expression in human OA synovial and medial tibial plateau tissue. In rats, synovial expression of ALX was positively correlated with expression of IL‐1β, tumor necrosis factor, and cyclooxygenase 2. Treatment with 17(R)‐HDoHE reversed established pain behavior (but not joint pathology) in 2 models of OA pain. This was associated with a significant elevation in the plasma levels of resolvin D2 and a significant reduction in astrogliosis in the spinal cord in the monosodium iodoacetate–induced OA rat model.ConclusionOur preclinical data demonstrate the robust analgesic effects of activation of the D series resolvin pathways in 2 different animal models of OA. Our data support a predominant central mechanism of action in clinically relevant models of OA pain.

Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators

“…AT-RvD1 reduces osteoarthritic pain (139), as does precursor 17-HDHA (140), prompting validation of their receptors (ALX/ FPR2 and ERV/CMKLR1) in rat models of osteoarthritis pain (141). Plasma RvD2 levels correlate with reduction in astrogliosis in spinal cord (141).…”

“…AT-RvD1 reduces osteoarthritic pain (139), as does precursor 17-HDHA (140), prompting validation of their receptors (ALX/ FPR2 and ERV/CMKLR1) in rat models of osteoarthritis pain (141). Plasma RvD2 levels correlate with reduction in astrogliosis in spinal cord (141). Fish consumption by humans, which increases plasma SPMs and precursors, reduces rheumatoid arthritis (RA) disease activity (142), and omega-3 fatty acid supplementation increases 18-HEPE and 17-HDHA, as well as RvEs, PD1, PDX, MaR1, and RvDs in plasma and synovial fluid (143).…”

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

“…Exogenous 17-HDHA halted progression of pain behaviour in a surgical model of OA pain 17 . However, 17-HDHA did not alter the extent of joint pathology, pointing to potential direct effects on sensory nerves or in the central nervous system and suggesting the therapeutic potential of this new class of analgesics for the treatment of OA pain.…”

Peripheral Interaction of Resolvin D1 and E1 with Opioid Receptor Antagonists for Antinociception in Inflammatory Pain in Rats

“…For example, intrathecal application of RvD1 and RvE1 increases thermal nociceptive thresholds after CFA (Xu et al, 2010 ). Spinal RvD1 elicits potent antinociceptive effect in lumbar disc herniation (Liu et al, 2016 ), prevents long-term hypersensitivity after thoracotomy (Wang and Strichartz, 2017 ) as well as chronic pancreatitis-induced visceral pain (Quan-Xin et al, 2012 ) and 17(R)-HDoHE reverses pain behavior in two models of osteoarthritis pain (Huang et al, 2017 ). Less is known about peripheral effects and about mechanical hypersensitivity: intraplantar RvD1 and RvE1 reduced carrageen-induced thermal hypersensitivity and pain behavior evoked by capsaicin or AITC, respectively (Park et al, 2011b ).…”

“…Resolvins are lipid mediators that rise during resolution of acute inflammation from poly-unsaturated fatty acids and docosahexanoic acid (Serhan, 2014 ). Resolvins such as resolvin D1 (RvD1) and resolvin E1 (RvE1) facilitate the resolution of inflammation (Ji et al, 2011 ) in, for example, sepsis, asthma, atherosclerosis, and osteoarthritis (Merched et al, 2008 ; Xu and Ji, 2011 ; Chiang et al, 2015 ; Provoost et al, 2016 ; Huang et al, 2017 ). All known resolvin receptors are G protein-coupled receptors (GPCR).…”