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Augmented pain behavioural responses to intra-articular injection of nerve growth factor in two animal models of osteoarthritis
  1. Sadaf Ashraf1,2,3,
  2. Paul Ian Mapp1,2,
  3. James Burston1,4,
  4. Andrew John Bennett4,
  5. Victoria Chapman1,4,
  6. David Andrew Walsh1,2
  1. 1Arthritis Research UK Pain Centre, University of Nottingham, Nottingham, UK
  2. 2Department of Academic Rheumatology, University of Nottingham, Nottingham, UK
  3. 3Centre for Vision and Vascular Sciences, Institute of Clinical Science, Royal Victoria Hospital, Belfast, UK
  4. 4School of Biomedical Sciences, University of Nottingham, Nottingham, UK
  1. Correspondence to Professor David Walsh, Arthritis Research UK Pain Centre, Department of Academic Rheumatology, University of Nottingham, City Hospital, Clinical Sciences Building, Hucknall Road, Nottingham NG5 1PB, UK, david.walsh{at}nottingham.ac.uk

Abstract

Objectives 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.

  • Knee Osteoarthritis
  • Corticosteroids
  • Synovitis

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