Zimmermann Katharina, Leffler Andreas, Babes Alexandru, Cendan Cruz Miguel, Carr Richard W, Kobayashi Jin-ichi, Nau Carla, Wood John N, Reeh Peter W
Department of Physiology and Pathophysiology, Faculty of Medicine, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
Nature. 2007 Jun 14;447(7146):855-8. doi: 10.1038/nature05880.
Sensory acuity and motor dexterity deteriorate when human limbs cool down, but pain perception persists and cold-induced pain can become excruciating. Evolutionary pressure to enforce protective behaviour requires that damage-sensing neurons (nociceptors) continue to function at low temperatures. Here we show that this goal is achieved by endowing superficial endings of slowly conducting nociceptive fibres with the tetrodotoxin-resistant voltage-gated sodium channel (VGSC) Na(v)1.8 (ref. 2). This channel is essential for sustained excitability of nociceptors when the skin is cooled. We show that cooling excitable membranes progressively enhances the voltage-dependent slow inactivation of tetrodotoxin-sensitive VGSCs. In contrast, the inactivation properties of Na(v)1.8 are entirely cold-resistant. Moreover, low temperatures decrease the activation threshold of the sodium currents and increase the membrane resistance, augmenting the voltage change caused by any membrane current. Thus, in the cold, Na(v)1.8 remains available as the sole electrical impulse generator in nociceptors that transmits nociceptive information to the central nervous system. Consistent with this concept is the observation that Na(v)1.8-null mutant mice show negligible responses to noxious cold and mechanical stimulation at low temperatures. Our data present strong evidence for a specialized role of Na(v)1.8 in nociceptors as the critical molecule for the perception of cold pain and pain in the cold.
当人体四肢冷却时，感觉敏锐度和运动敏捷度会下降，但疼痛感知依然存在，而且冷诱导的疼痛会变得极其剧烈。促使保护性反应的进化压力要求损伤感应神经元（伤害感受器）在低温下仍能继续发挥作用。在此，我们表明，这一目标是通过赋予传导缓慢的伤害性纤维的浅表末梢对河豚毒素耐受的电压门控钠通道（VGSC）Na(v)1.8来实现的（参考文献2）。当皮肤冷却时，该通道对于伤害感受器的持续兴奋性至关重要。我们发现，冷却可兴奋膜会逐渐增强河豚毒素敏感的VGSCs的电压依赖性缓慢失活。相比之下，Na(v)1.8的失活特性完全抗冷。此外，低温会降低钠电流的激活阈值并增加膜电阻，从而增大由任何膜电流引起的电压变化。因此，在寒冷环境中，Na(v)1.8作为伤害感受器中唯一将伤害性信息传递至中枢神经系统的电冲动发生器，依然可用。与这一概念相符的是，观察发现Na(v)1.8基因敲除的突变小鼠在低温下对有害冷刺激和机械刺激的反应微乎其微。我们的数据为Na(v)1.8在伤害感受器中作为冷痛和寒冷环境中疼痛感知的关键分子的特殊作用提供了有力证据。
