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Blocking the tropomyosin receptor kinase A (TrkA) receptor inhibits pain behaviour in two rat models of osteoarthritis

Nwosu, Lilian Ngozi; Mapp, Paul I.; Chapman, Victoria; Walsh, David A.

Authors

Lilian Ngozi Nwosu mbxlnn@nottingham.ac.uk

Paul I. Mapp

David A. Walsh



Abstract

Objectives: Tropomyosin receptor kinase A (TrkA) mediates nociceptor sensitisation by nerve growth factor (NGF), but it is unknown whether selective TrkA inhibition will be an effective strategy for treating osteoarthritis (OA) pain. We determined the effects of a TrkA inhibitor (AR786) on pain behaviour, synovitis and joint pathology in two rat OA models.
Methods: Knee OA was induced in rats by intraarticular monosodium-iodoacetate (MIA) injection or meniscal transection (MNX) and compared with saline injected or sham-operated controls. Pain behaviour was assessed as weight-bearing asymmetry and paw withdrawal threshold to punctate stimulation. Oral doses (30 mg/kg) of AR786 or vehicle were administered twice daily in either preventive (day −1 to –27) or treatment (day 14–28) protocols. Effect maintenance was evaluated for 2 weeks after treatment discontinuation. Alterations in knee structure (cartilage, subchondral bone and synovium) were examined by macroscopic visualisation of articular surfaces and histopathology.
Results: Preventive AR786 treatment inhibited pain behaviour development and therapeutic treatment attenuated established pain behaviour. Weight-bearing asymmetry increased 1 week after treatment discontinuation, but remained less than in vehicle- treated arthritic rats, whereas paw withdrawal thresholds returned to levels of untreated rats within 5 days of treatment discontinuation. AR786 treatment reduced MIA-induced synovitis and did not significantly affect osteochondral pathology in either model.
Conclusions: Blocking NGF activity by inhibiting TrkA reduced pain behaviour in two rat models of OA. Analgesia was observed both using preventive and treatment protocols, and was sustained after treatment discontinuation. Selective inhibitors of TrkA therefore hold potential for OA pain relief.

Journal Article Type Article
Journal Annals of the Rheumatic Diseases
Print ISSN 0003-4967
Electronic ISSN 1468-2060
Publisher BMJ Publishing Group
Peer Reviewed Peer Reviewed
Volume 75
Issue 6
APA6 Citation Nwosu, L. N., Mapp, P. I., Chapman, V., & Walsh, D. A. (in press). Blocking the tropomyosin receptor kinase A (TrkA) receptor inhibits pain behaviour in two rat models of osteoarthritis. Annals of the Rheumatic Diseases, 75(6), https://doi.org/10.1136/annrheumdis-2014-207203
DOI https://doi.org/10.1136/annrheumdis-2014-207203
Publisher URL http://ard.bmj.com/content/75/6/1246.long
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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