Modulation of Voltage-Gated Sodium Channels by Activation of Tumor Necrosis Factor Receptor-1 and Receptor-2 in Small DRG Neurons of Rats.
Modulation of Voltage-Gated Sodium Channels by Activation of Tumor Necrosis Factor Receptor-1 and Receptor-2 in Small DRG Neurons of Rats.
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DOI：
10.1155/2015/124942
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发表时间：
2015
影响因子：
4.6
通讯作者：
Hagenacker T
中科院分区：
文献类型：
--
作者：
Leo M;Argalski S;Schäfers M;Hagenacker T
肿瘤坏死因子-α（TNF-α）是一种促炎细胞因子，参与炎性和神经性疼痛的发生和维持。其作用由两种受体介导，TNF受体-1（TNFR-1）和TNF受体-2（TNFR-2）。这些受体在电压门控钠通道（VGSC）的敏化中起着至关重要的作用，这是慢性疼痛发病机制的关键机制。采用全细胞膜片钳技术，我们研究了TNFR-1和TNFR-2对大鼠背根神经节神经元VGSC和TTX抗性NaV1.8通道的影响。TNFR-1激动剂R32 W（10 pg/mL）使VGSC电流（I Na（V））增加27.2 ± 5.1%，而TNFR-2激动剂D145（10 pg/mL）使电流增加44.9 ± 2.6%。该效应具有剂量依赖性。用R32 W（100 pg/mL）处理分离的NaV 1.8导致I NaV（1.8）增加18.9 ± 1.6%，而用D145（100 pg/mL）处理使电流增加14.5 ± 3.7%。基于电流-电压关系，10 pg的R32 W或D145导致I Na（V）以钟形电压依赖性方式增加，在−30 mV时效应最大。TNFR激活对VGSC的影响促进初级传入神经元的兴奋，这可能解释了与神经病理性疼痛和炎性疼痛相关的致敏机制。
Tumor necrosis factor- (TNF-) α is a proinflammatory cytokine involved in the development and maintenance of inflammatory and neuropathic pain. Its effects are mediated by two receptors, TNF receptor-1 (TNFR-1) and TNF receptor-2 (TNFR-2). These receptors play a crucial role in the sensitization of voltage-gated sodium channels (VGSCs), a key mechanism in the pathogenesis of chronic pain. Using the whole-cell patch-clamp technique, we examined the influence of TNFR-1 and TNFR-2 on VGSCs and TTX-resistant NaV1.8 channels in isolated rat dorsal root ganglion neurons by using selective TNFR agonists. The TNFR-1 agonist R32W (10 pg/mL) caused an increase in the VGSC current (I Na(V)) by 27.2 ± 5.1%, while the TNFR-2 agonist D145 (10 pg/mL) increased the current by 44.9 ± 2.6%. This effect was dose dependent. Treating isolated NaV1.8 with R32W (100 pg/mL) resulted in an increase in I NaV(1.8) by 18.9 ± 1.6%, while treatment with D145 (100 pg/mL) increased the current by 14.5 ± 3.7%. Based on the current-voltage relationship, 10 pg of R32W or D145 led to an increase in I Na(V) in a bell-shaped, voltage-dependent manner with a maximum effect at −30 mV. The effects of TNFR activation on VGSCs promote excitation in primary afferent neurons and this might explain the sensitization mechanisms associated with neuropathic and inflammatory pain.