Département de Pharmacologie et Physiologie, Institut de pharmacologie de Sherbrooke, Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Faculté de médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada.
Physiol Rep. 2021 Aug;9(16):e14975. doi: 10.14814/phy2.14975.
Voltage-gated ion channels play a key role in the action potential (AP) initiation and its propagation in sensory neurons. Modulation of their activity during chronic inflammation creates a persistent pain state. In this study, we sought to determine how peripheral inflammation caused by complete Freund's adjuvant (CFA) alters the fast sodium (I ), L-type calcium (I ), and potassium (I ) currents in primary afferent fibers to increase nociception. In our model, intraplantar administration of CFA induced mechanical allodynia and thermal hyperalgesia at day 14 post-injection. Using whole-cell patch-clamp recording in dissociated small (C), medium (Aδ), and large-sized (Aβ) rat dorsal root ganglion (DRG) neurons, we found that CFA prolonged the AP duration and increased the amplitude of the tetrodotoxin-resistant (TTX-r) I in Aβ fibers. In addition, CFA accelerated the recovery of I from inactivation in C and Aδ nociceptive fibers but enhanced the late sodium current (I ) only in Aδ and Aβ neurons. Inflammation similarly reduced the amplitude of I in each neuronal cell type. Fourteen days after injection, CFA reduced both components of I (I and I ) in Aδ fibers. We also found that I was significantly larger in C and Aδ neurons in normal conditions and during chronic inflammation. Our data, therefore, suggest that targeting the transient potassium current I represents an efficient way to shift the balance toward antinociception during inflammation, since its activation will selectively decrease the AP duration in nociceptive fibers. Altogether, our data indicate that complex interactions between I , I , and I reduce pain threshold by concomitantly enhancing the activity of nociceptive neurons and reducing the inhibitory action of Aβ fibers during chronic inflammation.
电压门控离子通道在感觉神经元的动作电位 (AP) 起始及其传播中起着关键作用。在慢性炎症期间，其活性的调节会产生持续的疼痛状态。在这项研究中，我们试图确定完全弗氏佐剂 (CFA) 引起的外周炎症如何改变初级传入纤维中的快速钠 (I)、L 型钙 (I) 和钾 (I) 电流，以增加伤害感受。在我们的模型中，足底内注射 CFA 会在注射后 14 天引起机械性痛觉过敏和热痛觉过敏。使用全细胞膜片钳记录分离的小 (C)、中 (Aδ) 和大 (Aβ) 大鼠背根神经节 (DRG) 神经元，我们发现 CFA 延长了 AP 持续时间并增加了 Aβ纤维中河豚毒素抗性 (TTX-r) I 的幅度。此外，CFA 加速了 C 和 Aδ 伤害感受纤维中 I 失活后的恢复，但仅在 Aδ 和 Aβ 神经元中增强了晚期钠电流 (I)。炎症同样减少了每种神经元细胞类型中 I 的幅度。注射后 14 天，CFA 减少了 Aδ 纤维中 I 的两个组成部分 (I 和 I)。我们还发现，在正常情况下和慢性炎症期间，I 在 C 和 Aδ 神经元中明显更大。因此，我们的数据表明，靶向瞬时钾电流 I 代表一种在炎症期间向抗伤害感受转变的有效方法，因为其激活将选择性地减少伤害感受纤维中的 AP 持续时间。总的来说，我们的数据表明，I、I 和 I 之间的复杂相互作用通过同时增强伤害感受神经元的活性和减少慢性炎症期间 Aβ 纤维的抑制作用来降低疼痛阈值。
