Nwosu Lilian N, Mapp Paul I, Chapman Victoria, Walsh David A
Arthritis Research UK Pain Centre, University of Nottingham, Nottingham, UK School of Medicine, University of Nottingham, Nottingham, UK.
Arthritis Research UK Pain Centre, University of Nottingham, Nottingham, UK School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
Ann Rheum Dis. 2016 Jun;75(6):1246-54. doi: 10.1136/annrheumdis-2014-207203. Epub 2015 Aug 18.
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.
Knee OA was induced in rats by intra-articular 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.
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.
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.
原肌球蛋白受体激酶A（TrkA）介导神经生长因子（NGF）引起的伤害感受器致敏，但选择性抑制TrkA是否为治疗骨关节炎（OA）疼痛的有效策略尚不清楚。我们在两种大鼠OA模型中确定了TrkA抑制剂（AR786）对疼痛行为、滑膜炎和关节病理的影响。
通过关节内注射碘乙酸钠（MIA）或半月板横断（MNX）诱导大鼠膝OA，并与注射生理盐水或假手术对照组进行比较。疼痛行为通过负重不对称和对点状刺激的爪退缩阈值进行评估。AR786或赋形剂的口服剂量（30mg/kg）每天给药两次，采用预防性（第-1至-27天）或治疗性（第14至28天）方案。在停药后2周评估效果维持情况。通过关节表面的宏观观察和组织病理学检查膝关节结构（软骨、软骨下骨和滑膜）的改变。
预防性AR786治疗可抑制疼痛行为的发展，治疗性治疗可减轻已确立的疼痛行为。停药1周后负重不对称增加，但仍低于赋形剂治疗的关节炎大鼠，而爪退缩阈值在停药后5天内恢复到未治疗大鼠的水平。AR786治疗可减轻MIA诱导的滑膜炎，且在两种模型中均未显著影响骨软骨病理。
通过抑制TrkA阻断NGF活性可减轻两种大鼠OA模型的疼痛行为。预防性和治疗性方案均观察到镇痛作用，且停药后仍持续存在。因此，TrkA的选择性抑制剂具有缓解OA疼痛的潜力。
