Namer Barbara, Ørstavik Kristin, Schmidt Roland, Kleggetveit Inge-Petter, Weidner Christian, Mørk Cato, Kvernebo Mari Skylstad, Kvernebo Knut, Salter Hugh, Carr Thomas Hedley, Segerdahl Märta, Quiding Hans, Waxman Stephen George, Handwerker Hermann Otto, Torebjörk Hans Erik, Jørum Ellen, Schmelz Martin
Department of Physiology and Pathophysiology, University of Erlangen, Erlangen, Germany Department of Neurology, Oslo University Hospital, Rikshospitalet, Oslo, Norway Department of Clinical Neurophysiology, University of Uppsala, Uppsala, Sweden Institute of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway Department of Rheumatology, Skin and Infectious Diseases, Oslo University Hospital, Oslo, Norway Department of Vascular Surgery, Oslo University Hospital, Oslo, Norway AstraZeneca Translational Science Centre, Department of Clinical Neuroscience, Karolinska Institutet, Sweden AstraZeneca R&D, Macclesfield, United Kingdom Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT, USA Department of Anesthesiology Mannheim, Heidelberg University, Heidelberg, Germany.
Pain. 2015 Sep;156(9):1637-1646. doi: 10.1097/j.pain.0000000000000229.
Seven patients diagnosed with erythromelalgia (EM) were investigated by microneurography to record from unmyelinated nerve fibers in the peroneal nerve. Two patients had characterized variants of sodium channel Nav1.7 (I848T, I228M), whereas no mutations of coding regions of Navs were found in 5 patients with EM. Irrespective of Nav1.7 mutations, more than 50% of the silent nociceptors in the patients with EM showed spontaneous activity. In the patient with mutation I848T, all nociceptors, but not sympathetic efferents, displayed enhanced early subnormal conduction in the velocity recovery cycles and the expected late subnormality was reversed to supranormal conduction. The larger hyperpolarizing shift of activation might explain the difference to the I228M mutation. Sympathetic fibers that lack Nav1.8 did not show supranormal conduction in the patient carrying the I848T mutation, confirming in human subjects that the presence of Nav1.8 crucially modulates conduction in cells expressing EM mutant channels. The characteristic pattern of changes in conduction velocity observed in the patient with the I848T gain-of function mutation in Nav1.7 could be explained by axonal depolarization and concomitant inactivation of Nav1.7. If this were true, activity-dependent hyperpolarization would reverse inactivation of Nav1.7 and account for the supranormal CV. This mechanism might explain normal pain thresholds under resting conditions.
对7例诊断为红斑性肢痛症（EM）的患者进行了微神经ography检查，以记录腓总神经中无髓神经纤维的情况。2例患者具有钠通道Nav1.7的特征性变体（I848T、I228M），而在5例EM患者中未发现Navs编码区的突变。无论Nav1.7是否突变，EM患者中超过50%的静息伤害感受器表现出自发活动。在携带I848T突变的患者中，所有伤害感受器而非交感传出纤维在速度恢复周期中表现出增强的早期亚正常传导，预期的晚期亚正常传导转变为超正常传导。激活的更大超极化偏移可能解释了与I228M突变的差异。缺乏Nav1.8的交感纤维在携带I848T突变的患者中未表现出超正常传导，在人体中证实Nav1.8的存在对表达EM突变通道的细胞中的传导起关键调节作用。在Nav1.7中具有I848T功能获得性突变的患者中观察到的传导速度变化的特征模式可以通过Nav1.7的轴突去极化和伴随的失活来解释。如果这是真的，活动依赖性超极化将逆转Nav1.7的失活并解释超正常CV。这种机制可能解释静息状态下正常的疼痛阈值。
