Anoctamin 1 contributes to inflammatory and nerve-injury induced hypersensitivity.
Anoctamin 1 contributes to inflammatory and nerve-injury induced hypersensitivity.
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DOI：
10.1186/1744-8069-10-5
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发表时间：
2014-01-23
期刊：
影响因子：
3.3
通讯作者：
Oh U
中科院分区：
文献类型：
--
作者：
Lee B;Cho H;Jung J;Yang YD;Yang DJ;Oh U
各种病理条件，如炎症或损伤可引起疼痛过敏。这代表了对无害刺激的反应或对有害刺激的夸张反应。疼痛超敏反应的分子机制与背根神经节（DRG）神经元中多种离子通道的改变有关。Anoctamin 1 （ANO1/TMEM16A）是Ca2+激活的氯离子通道，在小DRG神经元中高度可见，并对热作出反应。DRG神经元中ANO1功能缺失的小鼠在暴露于有害热量时表现出疼痛样行为的减弱，这表明ANO1在急性热伤害感觉中起作用。在这项研究中，我们进一步研究了ANO1在介导炎症或损伤引起的痛觉过敏或异常性疼痛中的功能。使用Adv/Ano1 fl/fl （Adv/Ano1 fl/fl）小鼠，主要在DRG神经元中有Ano1的功能性消融，我们能够确定其在介导炎症或神经损伤引起的热痛觉过敏和机械异常痛中的作用。Adv/Ano1 fl/fl小鼠的热痛觉过敏、机械性异常痛及余神经损伤均明显减轻。此外，Adv/Ano1 fl/fl小鼠注射缓激肽或福尔马林后的退缩或舔舐行为也显著减少。由于病理条件增强了伤害性行为，我们预计ANO1对DRG神经元的兴奋性有贡献。事实上，炎症介质的应用降低了从对照（Ano1 fl/fl）小鼠分离的DRG神经元的动作电位阈值（流变酶）或诱导第一动作电位的时间。炎症介质诱导的神经元兴奋性的这些参数在Adv/Ano1 fl/fl小鼠中没有改变，这表明Ano1在增强神经元兴奋性方面有积极的贡献。ANO1除了作为热传感器介导急性热痛的作用外，ANO1还能够在炎症或神经病状态下增强DRG神经元的兴奋性，从而加重炎症或组织损伤引起的病理性疼痛。
Various pathological conditions such as inflammation or injury can evoke pain hypersensitivity. That represents the response to innocuous stimuli or exaggerated response to noxious stimuli. The molecular mechanism based on the pain hypersensitivity is associated with changes in many of ion channels in dorsal-root ganglion (DRG) neurons. Anoctamin 1 (ANO1/TMEM16A), a Ca2+ activated chloride channel is highly visible in small DRG neurons and responds to heat. Mice with an abolished function of ANO1 in DRG neurons demonstrated attenuated pain-like behaviors when exposed to noxious heat, suggesting a role in acute thermal nociception. In this study, we further examined the function of ANO1 in mediating inflammation- or injury-induced hyperalgesia or allodynia. Using Advillin/Ano1 fl/fl (Adv/Ano1 fl/fl ) mice that have a functional ablation of Ano1 mainly in DRG neurons, we were able to determine its role in mediating thermal hyperalgesia and mechanical allodynia induced by inflammation or nerve injury. The thermal hyperalgesia and mechanical allodynia induced by carrageenan injection and spared-nerve injury were significantly reduced in Adv/Ano1 fl/fl mice. In addition, flinching or licking behavior after bradykinin or formalin injection was also significantly reduced in Adv/Ano1 fl/fl mice. Since pathological conditions augment nociceptive behaviors, we expected ANO1′s contribution to the excitability of DRG neurons. Indeed, the application of inflammatory mediators reduced the threshold for action potential (rheobase) or time for induction of the first action potential in DRG neurons isolated from control (Ano1 fl/fl ) mice. These parameters for neuronal excitability induced by inflammatory mediators were not changed in Adv/Ano1 fl/fl mice, suggesting an active contribution of ANO1 in augmenting the neuronal excitability. In addition to ANO1's role in mediating acute thermal pain as a heat sensor, ANO1 is also capable of augmenting the excitability of DRG neurons under inflammatory or neuropathic conditions and thereby aggravates inflammation- or tissue injury-induced pathological pain.
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缓激肽在大鼠感觉神经元中诱导的急性伤害性信号是通过抑制 M 型 K 通道和激活 Ca2 激活的 Cl 通道介导的
影响因子：
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