title: Augmented pain behavioural responses to intra-articular injection of nerve growth factor in two animal models of osteoarthritis.
abstract: OBJECTIVE
  Nerve growth factor (NGF) is a promising analgesic target, particularly in osteoarthritis (OA) where existing therapies are inadequate. We hypothesised that pain responses to NGF are increased in OA joints. Here, NGF-evoked pain behaviour was compared in two rodent models of OA, and possible mechanisms underlying altered pain responses were examined.
  
  
  METHODS
  OA was induced in rat knees by meniscal transection (MNX) or intra-articular monosodium iodoacetate injection (MIA). Once OA pathology was fully established (day 20), we assessed pain behaviour (hindlimb weight-bearing asymmetry and hindpaw mechanical withdrawal thresholds) evoked by intra-articular injection of NGF (10 µg). Possible mechanisms underlying alterations in NGF-induced pain behaviour were explored using indomethacin pretreatment, histopathological evaluation of synovitis, and rtPCR for NGF receptor (tropomyosin receptor kinase (Trk)-A) expression in dorsal root ganglia (DRG).
  
  
  RESULTS
  Both the MIA and MNX models of OA displayed reduced ipsilateral weight bearing and hindpaw mechanical withdrawal thresholds, mild synovitis and increased TrkA expression in DRG. NGF injection into OA knees produced a prolonged augmentation of weight-bearing asymmetry, compared to NGF injection in non-osteoarthritic knees. However, hindpaw mechanical withdrawal thresholds were not further decreased by NGF. Pretreatment with indomethacin attenuated NGF-facilitated weight-bearing asymmetry and reversed OA-induced ipsilateral TrkA mRNA up-regulation.
  
  
  CONCLUSIONS
  OA knees were more sensitive to NGF-induced pain behaviour compared to non-osteoarthritic knees. Cyclo-oxygenase products may contribute to increased TrkA expression during OA development, and the subsequent increased NGF sensitivity. Treatments that reduce sensitivity to NGF have potential to improve OA pain.
authors.affiliation: Arthritis Research UK Pain Centre, University of Nottingham, Nottingham, UK Department of Academic Rheumatology, University of Nottingham, Nottingham, UK Centre for Vision and Vascular Sciences, Institute of Clinical Science, Royal Victoria Hospital, Belfast, UK.
authors.forename: Sadaf
authors.initials: S
authors.lastname: Ashraf
authors.affiliation: Arthritis Research UK Pain Centre, University of Nottingham, Nottingham, UK Department of Academic Rheumatology, University of Nottingham, Nottingham, UK.
authors.forename: Paul Ian
authors.initials: PI
authors.lastname: Mapp
authors.affiliation: Arthritis Research UK Pain Centre, University of Nottingham, Nottingham, UK School of Biomedical Sciences, University of Nottingham, Nottingham, UK.
authors.forename: James
authors.initials: J
authors.lastname: Burston
authors.affiliation: School of Biomedical Sciences, University of Nottingham, Nottingham, UK.
authors.forename: Andrew John
authors.initials: AJ
authors.lastname: Bennett
authors.affiliation: Arthritis Research UK Pain Centre, University of Nottingham, Nottingham, UK School of Biomedical Sciences, University of Nottingham, Nottingham, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Chapman
authors.affiliation: Arthritis Research UK Pain Centre, University of Nottingham, Nottingham, UK Department of Academic Rheumatology, University of Nottingham, Nottingham, UK.
authors.forename: David Andrew
authors.initials: DA
authors.lastname: Walsh
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000378:metabolism; D007213:Indomethacin / Q000627:therapeutic use; D007270:Injections, Intra-Articular; D008297:Male; D020932:Nerve Growth Factor / Q000008:administration & dosage / Q000633:toxicity*; D010003:Osteoarthritis / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D010146:Pain / Q000139:chemically induced / Q000209:etiology*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000096:biosynthesis / Q000235:genetics; D013585:Synovitis / Q000139:chemically induced; D015854:Up-Regulation / Q000187:drug effects; D016474:Weight-Bearing / Q000502:physiology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D012333:RNA, Messenger; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D007213:Indomethacin
keywords: Corticosteroids; Knee Osteoarthritis; Synovitis