Pyrethroids inhibit K2P channels and activate sensory neurons: basis of insecticide-induced paraesthesias.
Pyrethroids inhibit K2P channels and activate sensory neurons: basis of insecticide-induced paraesthesias.
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DOI：
10.1097/j.pain.0000000000001068
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发表时间：
2018-01
期刊：
影响因子：
7.4
通讯作者：
Gasull X
中科院分区：
文献类型：
--
作者：
Castellanos A;Andres A;Bernal L;Callejo G;Comes N;Gual A;Giblin JP;Roza C;Gasull X
补充数字内容在文本中可用。拟除虫菊酯类杀虫剂抑制K2 P钾通道有助于激活初级感觉神经元，引起感觉异常和疼痛感觉。拟除虫菊酯杀虫剂广泛用于农业害虫控制或人类公共卫生，通常作为疥疮和头虱的局部治疗。暴露于拟除虫菊酯（如氯菊酯或胺菊酯（TM））会导致感觉改变，如短暂性疼痛、烧灼感、刺痛感和感觉异常。尽管拟除虫菊酯对钠通道的作用众所周知，但对控制感觉神经元兴奋性的其他通道的作用研究较少。鉴于2孔结构域钾（K2 P）通道在生理和病理条件下调节感觉神经元兴奋性和放电的作用，我们研究了拟除虫菊酯对主要表达于感觉神经元的K2 P通道的影响。通过电生理和钙成像实验，我们表明，高比例的TM响应神经元的伤害感受器，这也被激活的TRPA 1和/或TRPV 1激动剂。这种拟除虫菊酯还激活和增强外周隐神经纤维的兴奋性。拟除虫菊酯对天然TRESK、TRAAK、TREK-1和TREK-2电流产生显著抑制。在转染的HEK 293细胞中发现了类似的效果。在行为水平，在小鼠爪中的皮内TM注射产生伤害性反应并引起机械异常性疼痛，表明在培养物中对伤害感受器的影响导致体内疼痛相关行为。在TRESK基因敲除小鼠中，TM引起的疼痛相关行为增强，为该通道在防止过度神经元激活中的作用提供了进一步的证据。我们的研究结果表明，抑制K2 P通道有利于感觉神经元的激活，并增加其兴奋性。这些影响导致拟除虫菊酯暴露后产生感觉异常和疼痛。
Supplemental Digital Content is Available in the Text. Inhibition of K2P potassium channels by pyrethroid insecticides contribute to activate primary sensory neurons to cause paraesthesias and painful sensations. Pyrethroid insecticides are widely used for pest control in agriculture or in human public health commonly as a topical treatment for scabies and head lice. Exposure to pyrethroids such as permethrin or tetramethrin (TM) causes sensory alterations such as transient pain, burning, stinging sensations, and paraesthesias. Despite the well-known effects of pyrethroids on sodium channels, actions on other channels that control sensory neuron excitability are less studied. Given the role of 2-pore domain potassium (K2P) channels in modulating sensory neuron excitability and firing, both in physiological and pathological conditions, we examined the effect of pyrethroids on K2P channels mainly expressed in sensory neurons. Through electrophysiological and calcium imaging experiments, we show that a high percentage of TM-responding neurons were nociceptors, which were also activated by TRPA1 and/or TRPV1 agonists. This pyrethroid also activated and enhanced the excitability of peripheral saphenous nerve fibers. Pyrethroids produced a significant inhibition of native TRESK, TRAAK, TREK-1, and TREK-2 currents. Similar effects were found in transfected HEK293 cells. At the behavioral level, intradermal TM injection in the mouse paw produced nocifensive responses and caused mechanical allodynia, demonstrating that the effects seen on nociceptors in culture lead to pain-associated behaviors in vivo. In TRESK knockout mice, pain-associated behaviors elicited by TM were enhanced, providing further evidence for a role of this channel in preventing excessive neuronal activation. Our results indicate that inhibition of K2P channels facilitates sensory neuron activation and increases their excitability. These effects contribute to the generation of paraesthesias and pain after pyrethroid exposure.
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影响因子：
4.8
作者：
Czirjak, Gabor;Enyedi, Peter
通讯作者：
Enyedi, Peter
DOI：
10.1523/jneurosci.4666-09.2010
发表时间：
2010-03-24
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Lennertz RC;Tsunozaki M;Bautista DM;Stucky CL
通讯作者：
Stucky CL
伤害感受神经元体膜电位的控制及其对外周伤害感受传递的影响。
影响因子：
7.4
作者：
Du X;Hao H;Gigout S;Huang D;Yang Y;Li L;Wang C;Sundt D;Jaffe DB;Zhang H;Gamper N
通讯作者：
Gamper N
影响因子：
2.5
作者：
Ma, C;Shu, YS;LaMotte, RH
通讯作者：
LaMotte, RH
影响因子：
3.4
作者：
Motomura, H;Narahashi, T
通讯作者：
Narahashi, T