Selective inhibition of tropomyosin-receptor-kinase A (TrkA) reduces pain and joint damage in two rat models of inflammatory arthritis.
Selective inhibition of tropomyosin-receptor-kinase A (TrkA) reduces pain and joint damage in two rat models of inflammatory arthritis.
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DOI：
10.1186/s13075-016-0996-z
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发表时间：
2016-05-04
影响因子：
4.9
通讯作者：
Walsh DA
中科院分区：
文献类型：
--
作者：
Ashraf S;Bouhana KS;Pheneger J;Andrews SW;Walsh DA
炎症是关节炎疼痛的重要组成部分。神经生长因子（NGF）在急性和慢性疼痛状态中起着关键作用，特别是与炎症相关的疼痛。NGF通过原肌球蛋白受体激酶A（TrkA）起作用。在临床试验中，神经生长因子阻断剂减少了关节炎疼痛。我们探讨了关节内的机制，这可能有助于通过选择性抑制角叉菜胶诱导或胶原诱导的关节疼痛行为中的TrkA的NGF的镇痛作用。本研究的目的是阐明炎症是否是神经生长因子阻断疗效的核心。大鼠左膝注射2%角叉菜胶或生理盐水。通过皮内注射牛II型胶原（0.2mg）和不完全弗氏佐剂（0.2mg）的混合物诱导胶原诱导的关节炎（CIA）。在关节炎诱导后每天两次给予口服剂量（30 mg/kg）的AR 786或媒介物对照。使用布洛芬治疗（35 mg/kg，口服，每天一次）的CIA大鼠作为阳性镇痛对照。疼痛行为被测量为后肢负重不对称性和后爪回缩阈值到von Frey毛发刺激（角叉菜胶滑膜炎），或回缩到使用Randall Selitto装置（CIA）的关节压缩。炎症通过膝关节直径增加和组织病理学分析来测量。关节内注射角叉菜胶或诱导CIA均与疼痛行为和滑膜炎症相关。全身施用TrkA抑制剂AR 786将角叉菜胶诱导或CIA诱导的疼痛行为降低至对照值，并抑制关节肿胀和滑膜炎症和关节损伤的组织学证据。通过使用两种不同炎症的模型，我们首次证明了选择性抑制TrkA可以减少大鼠中角叉菜胶诱导或CIA诱导的疼痛行为，部分是通过潜在地抑制滑膜炎症，尽管对感觉神经的直接影响也是可能的。我们的观察结果表明，炎症性关节炎引起疼痛，炎症的存在是NGF阻断的有益作用（减轻疼痛和病理）的基础。进一步的研究应该确定TrkA抑制是否可以改善人类炎症性关节炎。
Inflammation is an essential component of arthritis pain. Nerve growth factor (NGF) plays a key role in acute and chronic pain states especially those associated with inflammation. NGF acts through tropomyosin-receptor-kinase A (TrkA). NGF blockade has reduced arthritis pain in clinical trials. We explored the mechanisms within the joint which may contribute to the analgesic effects of NGF by selectively inhibiting TrkA in carrageenan-induced or collagen-induced joint pain behaviour. The goal of the current study was to elucidate whether inflammation is central to the efficacy for NGF blockade. Rats were injected in their left knees with 2 % carrageenan or saline. Collagen-induced arthritis (CIA) was induced by intradermal injections of a mixture of bovine type II collagen (0.2 mg) and incomplete Freund’s adjuvant (0.2 mg). Oral doses (30 mg/kg) of AR786 or vehicle control were given twice daily after arthritis induction. Ibuprofen-treated (35 mg/kg, orally, once daily) rats with CIA were used as positive analgesic controls. Pain behaviour was measured as hind-limb weight-bearing asymmetry and hind-paw withdrawal thresholds to von Frey hair stimulation (carrageenan synovitis), or withdrawal to joint compression using a Randall Selitto device (CIA). Inflammation was measured as increased knee joint diameter and by histopathological analysis. Intra-articular injections of carrageenan or induction of CIA was each associated with pain behaviour and synovial inflammation. Systemic administration of the TrkA inhibitor AR786 reduced carrageenan-induced or CIA-induced pain behaviour to control values, and inhibited joint swelling and histological evidence of synovial inflammation and joint damage. By using two models of varying inflammation we demonstrate for the first time that selective inhibition of TrkA may reduce carrageenan-induced or CIA-induced pain behaviour in rats, in part through potentially inhibiting synovial inflammation, although direct effects on sensory nerves are also likely. Our observations suggest that inflammatory arthritis causes pain and the presence of inflammation is fundamental to the beneficial effects (reduction in pain and pathology) of NGF blockade. Further research should determine whether TrkA inhibition may ameliorate human inflammatory arthritis.