title: Targeting the D Series Resolvin Receptor System for the Treatment of Osteoarthritis Pain.
abstract: Pain 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.
  
  
  
  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.
  
  
  
  There 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.
  
  
  
  Our 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.
authors.affiliation: University of Nottingham, Nottingham, UK.
authors.forename: Junting
authors.initials: J
authors.lastname: Huang
authors.affiliation: University of Nottingham, Nottingham, UK.
authors.forename: James J
authors.initials: JJ
authors.lastname: Burston
authors.affiliation: University of Nottingham, Nottingham, UK.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: University of Nottingham, Nottingham, UK.
authors.forename: Sadaf
authors.initials: S
authors.lastname: Ashraf
authors.affiliation: University of Nottingham, Nottingham, UK.
authors.forename: Paul I
authors.initials: PI
authors.lastname: Mapp
authors.affiliation: University of Nottingham, Nottingham, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bennett
authors.affiliation: University of Nottingham, Nottingham, UK.
authors.forename: Srinivasarao
authors.initials: S
authors.lastname: Ravipati
authors.affiliation: University of Nottingham, Nottingham, UK.
authors.forename: Petros
authors.initials: P
authors.lastname: Pousinis
authors.affiliation: University of Nottingham, Nottingham, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Barrett
authors.affiliation: University of Nottingham, Nottingham, UK.
authors.forename: Brigitte E
authors.initials: BE
authors.lastname: Scammell
authors.affiliation: University of Nottingham, Nottingham, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Chapman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D018771:Arthralgia / Q000139:chemically induced; D001522:Behavior, Animal / Q000187:drug effects*; D002358:Cartilage, Articular / Q000473:pathology; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000633:toxicity; D015870:Gene Expression; D006801:Humans; D019807:Iodoacetic Acid / Q000633:toxicity; D008592:Menisci, Tibial / Q000601:surgery; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D020370:Osteoarthritis, Knee / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D019707:Receptors, Chemokine / Q000187:drug effects / Q000235:genetics*; D044067:Receptors, Lipoxin / Q000187:drug effects / Q000235:genetics; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism; D013583:Synovial Membrane / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C102741:CMKLR1 protein, human; C109811:Cmklr1 protein, rat; D004791:Enzyme Inhibitors; C442142:HSH2D protein, human; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D044067:Receptors, Lipoxin; C482540:lipoxin A(4) receptor, rat; D004281:Docosahexaenoic Acids; C062894:17-hydroxy-4,7,10,13,15,19-docosahexaenoic acid; D019807:Iodoacetic Acid