A microfluidic-based model of nociceptor sensitization reveals a direct activation of sensory axons by prostaglandin E2
A microfluidic-based model of nociceptor sensitization reveals a direct activation of sensory axons by prostaglandin E2
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基于微流体的伤害感受器敏化模型揭示了前列腺素 E2 对感觉轴突的直接激活
DOI：
10.1101/2022.03.18.484883
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Kimourtzis G
中科院分区：
文献类型：
--
作者：
Kimourtzis G
前列腺素E2 （PGE2）是炎症性痛觉过敏的主要因素之一，然而，它在多大程度上调节伤害性轴突的活动尚不完全清楚。我们使用微流控细胞培养平台研究PGE2处理后感觉轴突反应性的变化。我们发现，将PGE2应用于流体分离的轴突会导致它们对去极化刺激的反应增敏，而HCN通道阻滞剂zatebradine则会阻止这种增强。然而，出乎意料的是，我们还发现PGE2在轴突上的应用在感觉神经元中引发了直接和持续的尖峰活动。我们证明这种持续的活性是由于PGE2对轴突的直接去极化，它被Nav1.8钠通道阻滞剂抑制，但主要对Nav1.7通道阻滞剂无效。EP4受体抑制剂和cAMP合成阻滞剂可以消除轴突的持续活性和膜去极化。我们的数据表明，PGE2/EP4/cAMP通路在感觉轴突的持续去极化中达到顶峰，导致动作电位的产生传播到体细胞。因此，PGE2不仅介导伤害感受器致敏，而且可以直接引起伤害轴突的放电，从而重新定义其在炎症条件下作为疼痛介质的作用。前列腺素E2可以在没有任何有害刺激的情况下使痛觉轴突去极化，从而导致痛觉神经元的持续激活。
Prostaglandin E2 (PGE2) is one of the major contributors to inflammatory pain hyperalgesia, however, the extent to which it modulates the activity of the nociceptive axons is incompletely understood. We used a microfluidic cell culture platform to investigate the changes in responsiveness of sensory axons following treatment with PGE2. We show that the application of PGE2 to fluidically isolated axons leads to sensitization of their responses to depolarising stimuli, and the inclusion of zatebradine, a blocker of HCN channels, blocks this enhancement. However, unexpectedly, we also found that the application of PGE2 to the axons elicited a direct and persistent spiking activity in the sensory neurons. We demonstrate that this persistent activity is due to a direct depolarization of axons by PGE2, which is inhibited by Nav1.8 sodium channel blockers but is mainly refractory to Nav1.7 channel blockade. Both the persistent activity and the membrane depolarization in the axons are abolished by the EP4 receptor inhibitor and a blocker of cAMP synthesis. Our data indicate that PGE2/EP4/cAMP pathway culminates in a sustained depolarization in the sensory axons, leading to the generation of action potentials propagating to the soma. PGE2 therefore, not only mediates nociceptor sensitization but can directly elicit discharges in nociceptive axons, hence redefining its role as a pain mediator in inflammatory conditions.One Sentence SummaryProstaglandin E2 can depolarise nociceptive axons in the absence of any noxious stimuli leading to a sustained activation of pain sensing neurons.
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影响因子：
120.1
作者：
Melanie I. Brazil
通讯作者：
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影响因子：
2.5
作者：
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影响因子：
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作者：
COLERIDGE, HM;COLERIDGE, JCG;MORRISON, MA
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影响因子：
5.3
作者：
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影响因子：
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作者：
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通讯作者：
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