Dynamic changes in heat transducing channel TRPV1 expression regulate mechanically insensitive, heat sensitive C-fiber recruitment after axotomy and regeneration.
Dynamic changes in heat transducing channel TRPV1 expression regulate mechanically insensitive, heat sensitive C-fiber recruitment after axotomy and regeneration.
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DOI：
10.1523/jneurosci.3148-12.2012
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发表时间：
2012-12-05
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影响因子：
--
通讯作者：
Koerber HR
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文献类型：
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作者：
Jankowski MP;Soneji DJ;Ekmann KM;Anderson CE;Koerber HR
外周损伤导致小鼠中含有热传导TRPV 1通道的机械不敏感、热敏C纤维（CH）的患病率显著增加。我们最近发现，CH纤维的募集与GDNF家族神经营养因子artemin（GFR α 3）受体的表达增加有关，并且在体内抑制GFR α 3可防止在轴突切断后正常观察到的TRPV 1表达增加。在这里，我们已经直接测试了这一假设，即神经再生后功能性CH纤维的募集需要增强的TRPV1水平。我们利用体内siRNA介导的敲低来抑制损伤诱导的TRPV1表达，再加上离体记录来检查再生后不同功能定义的皮肤感觉神经元的反应特征和神经化学表型。我们证实，抑制TRPV1并不影响轴突切断引起的CPM热阈值的降低，但短暂地阻止CH神经元的募集。此外，TRPV1蛋白的恢复后，观察到的siRNA介导的抑制，这是与CH神经元募集伴随反弹。因此，TRPV 1表达的动态变化（而不是绝对水平）可能是CH神经元中观察到的功能改变的基础，并且可能有助于神经损伤后热痛觉过敏的发展。
Peripheral injury leads to a significant increase in the prevalence of mechanically insensitive, heat sensitive C-fibers (CH) that contain the heat transducing TRPV1 channel in mice. We have recently shown that this recruitment of CH fibers is associated with increased expression of the receptor for GDNF family neurotrophic factor artemin (GFRα3), and that in vivo inhibition of GFRα3 prevented the increase in TRPV1 expression normally observed following axotomy. Here we have directly tested the hypothesis that the recruitment of functional CH-fibers following nerve regeneration requires enhanced TRPV1 levels. We utilized in vivo siRNA-mediated knockdown to inhibit the injury-induced expression of TRPV1 coupled with ex-vivo recording to examine response characteristics and neurochemical phenotypes of different functionally defined cutaneous sensory neurons after regeneration. We confirmed that inhibition of TRPV1 did not affect the axotomy induced decrease in CPM heat threshold, but transiently prevented the recruitment of CH neurons. Moreover, a recovery of TRPV1 protein was observed following resolution of siRNA-mediated inhibition that was correlated with a concomitant rebound in CH neuron recruitment. Thus dynamic changes in TRPV1 expression, not absolute levels, may underlie the functional alterations observed in CH neurons and may contribute to the development of heat hyperalgesia after nerve injury.