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首页> 外文期刊>Journal of neuroinflammation >CC chemokine ligand 2 upregulates the current density and expression of TRPV1 channels and Nav1.8 sodium channels in dorsal root ganglion neurons
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CC chemokine ligand 2 upregulates the current density and expression of TRPV1 channels and Nav1.8 sodium channels in dorsal root ganglion neurons

机译：CC趋化因子配体2上调背根神经节神经元TRPV1通道和Na v 1.8钠通道的电流密度和表达

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Background Inflammation or nerve injury-induced upregulation and release of chemokine CC chemokine ligand 2 (CCL2) within the dorsal root ganglion (DRG) is believed to enhance the activity of DRG nociceptive neurons and cause hyperalgesia. Transient receptor potential vanilloid receptor 1 (TRPV1) and tetrodotoxin (TTX)-resistant Nav1.8 sodium channels play an essential role in regulating the excitability and pain transmission of DRG nociceptive neurons. We therefore tested the hypothesis that CCL2 causes peripheral sensitization of nociceptive DRG neurons by upregulating the function and expression of TRPV1 and Nav1.8 channels. Methods DRG neuronal culture was prepared from 3-week-old Sprague–Dawley rats and incubated with various concentrations of CCL2 for 24 to 36 hours. Whole-cell voltage-clamp recordings were performed to record TRPV1 agonist capsaicin-evoked inward currents or TTX-insensitive Na+ currents from control or CCL2-treated small DRG sensory neurons. The CCL2 effect on the mRNA expression of TRPV1 or Nav1.8 was measured by real-time quantitative RT-PCR assay. Results Pretreatment of CCL2 for 24 to 36 hours dose-dependently (EC50 value?=?0.6?±?0.05 nM) increased the density of capsaicin-induced currents in small putative DRG nociceptive neurons. TRPV1 mRNA expression was greatly upregulated in DRG neurons preincubated with 5 nM CCL2. Pretreating small DRG sensory neurons with CCL2 also increased the density of TTX-resistant Na+ currents with a concentration-dependent manner (EC50 value?=?0.7?±?0.06 nM). The Nav1.8 mRNA level was significantly increased in DRG neurons pretreated with CCL2. In contrast, CCL2 preincubation failed to affect the mRNA level of TTX-resistant Nav1.9. In the presence of the specific phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002 or Akt inhibitor IV, CCL2 pretreatment failed to increase the current density of capsaicin-evoked inward currents or TTX-insensitive Na+ currents and the mRNA level of TRPV1 or Nav1.8. Conclusions Our results showed that CCL2 increased the function and mRNA level of TRPV1 channels and Nav1.8 sodium channels in small DRG sensory neurons via activating the PI3K/Akt signaling pathway. These findings suggest that following tissue inflammation or peripheral nerve injury, upregulation and release of CCL2 within the DRG could facilitate pain transmission mediated by nociceptive DRG neurons and could induce hyperalgesia by upregulating the expression and function of TRPV1 and Nav1.8 channels in DRG nociceptive neurons.
机译：背景技术炎症或神经损伤诱导的背根神经节（DRG）中趋化因子CC趋化因子配体2（CCL2）的上调和释放会增强DRG伤害感受神经元的活性并引起痛觉过敏。瞬态受体潜在的类香草酸受体1（TRPV1）和抗河豚毒素（TTX）的Nav1.8钠通道在调节DRG伤害感受神经元的兴奋性和疼痛传递中起着至关重要的作用。因此，我们测试了CCL2通过上调TRPV1和Nav1.8通道的功能和表达导致伤害性DRG神经元周围敏感的假设。方法从3周大的Sprague–Dawley大鼠制备DRG神经元培养物，并与各种浓度的CCL2孵育24至36小时。进行全细胞电压钳记录，以记录对照或经CCL2处理的小的DRG感觉神经元对TRPV1激动剂辣椒素诱发的内向电流或对TTX不敏感的Na +电流。通过实时定量RT-PCR测定来测量CCL2对TRPV1或Nav1.8的mRNA表达的影响。结果对CCL2进行24至36小时的剂量依赖性预处理（EC50值≥0.6±±0.05 nM）可以增加辣椒素诱导的小DRG伤害感受神经元的电流密度。在用5 nM CCL2预孵育的DRG神经元中，TRPV1 mRNA表达大大上调。用CCL2预处理小的DRG感觉神经元也以浓度依赖的方式增加了耐TTX的Na +电流的密度（EC50值≥0.7±±0.06 nM）。在用CCL2预处理的DRG神经元中，Nav1.8 mRNA水平显着增加。相反，CCL2预温育不能影响耐TTX的Nav1.9的mRNA水平。在存在特定的磷脂酰肌醇3激酶（PI3K）抑制剂LY294002或Akt抑制剂IV的情况下，CCL2预处理无法增加辣椒素诱发的内向电流或TTX敏感性Na +电流的电流密度以及TRPV1或Nav1.8的mRNA水平。 。结论我们的结果表明，CCL2通过激活PI3K / Akt信号通路提高了DRG小型感觉神经元TRPV1通道和Nav1.8钠通道的功能和mRNA水平。这些发现表明，在组织炎症或周围神经损伤后，DRG中CCL2的上调和释放可能促进伤害性DRG神经元介导的疼痛传递，并且可以通过上调DRG伤害性神经元中TRPV1和Nav1.8通道的表达和功能来诱导痛觉过敏。

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