Fischer Bradford D, Ho Cojen, Kuzin Igor, Bottaro Andrea, O'Leary Michael E
Cooper Medical School of Rowan University, Department of Biomedical Sciences,401 South Broadway, Camden, NJ 08103, United States.
Cooper Medical School of Rowan University, Department of Biomedical Sciences,401 South Broadway, Camden, NJ 08103, United States.
Neurosci Lett. 2017 Jul 13;653:195-201. doi: 10.1016/j.neulet.2017.05.004. Epub 2017 May 27.
The goal of these studies was to investigate the links between chronic exposure to the pro-inflammatory cytokine tumor necrosis factor (TNF), hyperalgesia and the excitability of dorsal root ganglion (DRG) sensory neurons. We employed transgenic mice that constitutively express TNF (TNFtg mice), a well-established model of chronic systemic inflammation. At 6 months of age, TNFtg mice demonstrated increased sensitivity to both mechanical and thermal heat stimulation relative to aged-matched wild-type controls. These increases in stimulus-evoked behaviors are consistent with nociceptor sensitization to normal physiological stimulation. The mechanisms underlying nociceptor sensitization were investigated using single-cell analysis to quantitatively compare gene expression in small-diameter (<30μm) DRG neurons. This analysis revealed the upregulation of mRNA encoding for tetrodotoxin-resistant (TTX-R) sodium (Na) channels (Nav1.8, Nav1.9), Na channel β subunits (β-β), TNF receptor 1 (TNFR1) and p38α mitogen-activated protein kinase in neurons of TNFtg mice. Whole-cell electrophysiology demonstrated a corresponding increase in TTX-R Na current density, hyperpolarizing shifts in activation and steady-state inactivation, and slower recovery from inactivation in the TNFtg neurons. Increased overlap of activation and inactivation in the TNFtg neurons produces inward Na currents at voltages near the resting membrane potential of sensory neurons (i.e. window currents). The combination of increased Na current amplitude, hyperpolarized shifts in Na channel activation and increased window current predicts a reduction in the action potential threshold and increased firing of small-diameter DRG neurons. Together, these data suggest that increases in the expression of Nav1.8 channels, regulatory β subunits and TNFR1 contribute to increased nociceptor excitability and hyperalgesia in the TNFtg mice.
这些研究的目的是调查长期暴露于促炎细胞因子肿瘤坏死因子（TNF）、痛觉过敏与背根神经节（DRG）感觉神经元兴奋性之间的联系。我们使用了组成性表达TNF的转基因小鼠（TNFtg小鼠），这是一种成熟的慢性全身性炎症模型。在6个月大时，与年龄匹配的野生型对照相比，TNFtg小鼠对机械和热刺激的敏感性增加。这些刺激诱发行为的增加与伤害感受器对正常生理刺激的敏化一致。使用单细胞分析来定量比较小直径（<30μm）DRG神经元中的基因表达，以研究伤害感受器敏化的潜在机制。该分析揭示了TNFtg小鼠神经元中编码河豚毒素抗性（TTX-R）钠（Na）通道（Nav1.8、Nav1.9）、Na通道β亚基（β-β）、TNF受体1（TNFR1）和p38α丝裂原活化蛋白激酶的mRNA上调。全细胞膜片钳电生理显示TNFtg神经元中TTX-R Na电流密度相应增加，激活和稳态失活出现超极化偏移，失活后恢复较慢。TNFtg神经元中激活和失活的重叠增加，在接近感觉神经元静息膜电位的电压下产生内向Na电流（即窗电流）。Na电流幅度增加、Na通道激活的超极化偏移和窗电流增加共同预示着动作电位阈值降低和小直径DRG神经元放电增加。总之，这些数据表明Nav1.8通道、调节性β亚基和TNFR1表达的增加导致了TNFtg小鼠伤害感受器兴奋性增加和痛觉过敏。
