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.
Highlights
Osteoarthritis (OA) is a highly prevalent degenerative joint disorder characterized by loss of cartilage, subchondral bone remodeling, and synovial inflammation [1,2]
OA pain is significantly associated with synovial inflammation and changes in the subchondral bone [4], and evidence of central sensitization and the spread of pain has been reported [5]
Expression of ChemR23 and ALX messenger RNA in the OA joint. Both ALX and ChemR23 were present in human synovium and medial tibial plateau bone obtained following total knee replacement (TKR) surgery for OA (Figures 1A and B)
Summary
Gene 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
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