Mechanosensitive ion channels in articular nociceptors drive mechanical allodynia in osteoarthritis
Mechanosensitive ion channels in articular nociceptors drive mechanical allodynia in osteoarthritis
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DOI：
10.1016/j.joca.2017.08.012
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发表时间：
2017-12-01
影响因子：
7
通讯作者：
Sharif-Naeini, R.
中科院分区：
文献类型：
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作者：
He, B. H.;Christin, M.;Sharif-Naeini, R.
目的：骨关节炎（OA）是一种致残和高度流行的疾病，影响全球数百万人。疼痛是OA患者的主要主诉，目前未得到充分管理。它表现为机械性异常性疼痛，对关节运动等无害刺激的疼痛反应。异常性疼痛部分是由于关节伤害感受器对机械刺激的敏感性。这些伤害感受器通过表达去极化高阈值机械敏感离子通道（MSIC）来响应施加到其末端的有害机械刺激，所述MSIC将疼痛的机械力转化为电信号。在这项研究中，我们研究的贡献MSICs机械异常性疼痛的小鼠模型OA.Method：单碘乙酸钠（MIA）注射在左膝的成年雄性Trpv1：Cre; GFP小鼠。使用屈膝试验监测原发性机械性异常性疼痛。单通道膜片钳电生理学进行视觉识别的膝关节神经支配的伤害性感受器。背角神经元激活评估Fos免疫反应性。结果：在检查门控性能的MSICs的幼稚和OA小鼠，我们发现，他们的激活阈值大大降低，导致他们的开放在显着较低的刺激强度。因此，伤害感受器被轻微的机械刺激激活。这些通道是可逆的抑制选择性MSIC抑制剂GsMTx4，和关节内注射这种肽显着减少了激活的背角伤害性回路和原发性机械异常性疼痛在OA mice. Conclusions：这些结果表明，MSIC致敏OA和直接有助于机械异常性疼痛。因此，它们代表了治疗OA疼痛的潜在治疗靶点。(C)2017国际骨关节炎研究学会。由爱思唯尔有限公司出版。保留所有权利。
Objective: Osteoarthritis (OA) is a disabling and highly prevalent condition affecting millions worldwide. Pain is the major complaint of OA patients and is presently inadequately managed. It manifests as mechanical allodynia, a painful response to innocuous stimuli such as joint movement. Allodynia is due in part to the sensitization of articular nociceptors to mechanical stimuli. These nociceptors respond to noxious mechanical stimuli applied to their terminals via the expression of depolarizing high-threshold mechanosensitive ion channels (MSICs) that convert painful mechanical forces into electrical signals. In this study, we examined the contribution of MSICs to mechanical allodynia in a mouse model of OA.Method: Sodium mono-iodoacetate (MIA) was injected in the left knee of adult male Trpv1:Cre; GFP mice. Primary mechanical allodynia was monitored using the knee-bend test. Single-channel patch clamp electrophysiology was performed on visually-identified knee-innervating nociceptors. Dorsal horn neuronal activation was assessed by Fos immunoreactivity.Results: In examining the gating properties of MSICs of naive and OA mice, we discovered that their activation threshold is greatly reduced, causing their opening at significantly lower stimuli intensities. Consequently, nociceptors are activated by mild mechanical stimuli. These channels are reversibly inhibited by the selective MSIC inhibitor GsMTx4, and the intra-articular injection of this peptide significantly reduced the activation of dorsal horn nociceptive circuits and primary mechanical allodynia in OA mice.Conclusions: These results suggest that MSICs are sensitized during OA and directly contribute to mechanical allodynia. They therefore represent potential therapeutic targets in the treatment of OA pain. (C) 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.