TRPM8, but not TRPA1, is required for neural and behavioral responses to acute noxious cold temperatures and cold-mimetics in vivo.
TRPM8, but not TRPA1, is required for neural and behavioral responses to acute noxious cold temperatures and cold-mimetics in vivo.
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DOI：
10.1016/j.pain.2010.05.021
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发表时间：
2010-08
期刊：
影响因子：
7.4
通讯作者：
McKemy DD
中科院分区：
文献类型：
--
作者：
Knowlton WM;Bifolck-Fisher A;Bautista DM;McKemy DD
躯体感觉神经元检测环境刺激，将外部线索转化为神经活动，该神经活动首先传递到脊髓中的二级神经元。冷的检测被认为是由离子通道TRPM 8和TRPA 1介导的。然而，关于每个通道在冷诱发疼痛中的作用存在重大争议，使其作为诸如冷异常性疼痛和痛觉过敏等病症的药物靶点的潜力复杂化。为了解决这一争论，我们产生了缺乏这两个通道的功能副本的小鼠，并检查了对疼痛的寒冷和有毒的冷却化合物的反应的行为和神经活动。尽管正常小鼠表现出对温暖的强烈偏好，但TRPM 8-null（TRPM 8-/-）和TRPM 8/TRPA 1双敲除小鼠（DKO）在温度达到极端有害范围之前没有表现出偏好。此外，与避免接触冷表面的野生型小鼠相反，缺乏TRPM 8通道的小鼠没有表现出这种回避，甚至在5°C下也会探索有害的冷表面。此外，对冷模拟icilin的伤害反应行为在TRPM 8 −/−和DKO小鼠中不存在，但在TRPA 1-nulls（TRPA 1 −/−）中保留。最后，通过立即早期基因c-fos的表达来测量的神经活动，在TRPM 8 −/−和DKO小鼠中，由有害的寒冷，薄荷醇或icilin刺激后爪引起的神经活动减少，但在TRPA 1 −/−动物中没有。因此，我们的研究结果表明，有害的冷信号是专为TRPM 8，介导神经和行为反应的冷和冷模拟，TRPA 1是不需要的哺乳动物急性冷痛。
Somatosensory neurons detect environmental stimuli, converting external cues into neural activity that is relayed first to second-order neurons in the spinal cord. The detection of cold is proposed to be mediated by the ion channels TRPM8 and TRPA1. However, there is significant debate regarding the role of each channel in cold-evoked pain, complicating their potential as drug targets for conditions such as cold allodynia and hyperalgesia. To address this debate, we generated mice lacking functional copies of both channels and examined behaviors and neural activity in response to painful cold and noxious cooling compounds. Whereas normal mice display a robust preference for warmth over cold, both TRPM8-null (TRPM8−/−) and TRPM8/TRPA1 double knockout mice (DKO) display no preference until temperatures reach the extreme noxious range. Additionally, in contrast to wildtype mice that avoid touching cold surfaces, mice lacking TRPM8 channels display no such avoidance and explore noxious cold surfaces, even at 5°C. Furthermore, nocifensive behaviors to the cold mimetic icilin are absent in TRPM8−/− and DKO mice, but are retained in TRPA1-nulls (TRPA1−/−). Lastly, neural activity, measured by expression of the immediate early gene c-fos, evoked by hindpaw stimulation with noxious cold, menthol, or icilin is reduced in TRPM8−/− and DKO mice, but not in TRPA1−/− animals. Thus our results show that noxious cold signaling is exclusive to TRPM8, mediating neural and behavioral responses to cold and cold mimetics, and that TRPA1 is not required for acute cold pain in mammals.
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影响因子：
16.2
作者：
Colburn, Raymond W.;Lubin, Mary Lou;Qin, Ning
通讯作者：
Qin, Ning
影响因子：
7.4
作者：
Berglund, B;Harju, EL;Lindblom, U
通讯作者：
Lindblom, U
影响因子：
5.3
作者：
Fajardo, Otto;Meseguer, Victor;Viana, Felix
通讯作者：
Viana, Felix
影响因子：
3.3
作者：
ABBADIE, C;HONORE, P;BESSON, JM
通讯作者：
BESSON, JM
DOI：
10.1085/jgp.200810136
发表时间：
2009-03
期刊：
The Journal of general physiology
影响因子：
--
作者：
Caspani O;Heppenstall PA
通讯作者：
Heppenstall PA