Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA, USA.
Department of OMNI Bioinformatics, Genentech, Inc., 1 DNA Way, South San Francisco, CA, USA.
Neuron. 2023 Sep 6;111(17):2642-2659.e13. doi: 10.1016/j.neuron.2023.05.024. Epub 2023 Jun 22.
Loss-of-function mutations in Nav1.7, a voltage-gated sodium channel, cause congenital insensitivity to pain (CIP) in humans, demonstrating that Nav1.7 is essential for the perception of pain. However, the mechanism by which loss of Nav1.7 results in insensitivity to pain is not entirely clear. It has been suggested that loss of Nav1.7 induces overexpression of enkephalin, an endogenous opioid receptor agonist, leading to opioid-dependent analgesia. Using behavioral pharmacology and single-cell RNA-seq analysis, we find that overexpression of enkephalin occurs only in cLTMR neurons, a subclass of sensory neurons involved in low-threshold touch detection, and that this overexpression does not play a role in the analgesia observed following genetic removal of Nav1.7. Furthermore, we demonstrate using laser speckle contrast imaging (LSCI) and in vivo electrophysiology that Nav1.7 function is required for the initiation of C-fiber action potentials (APs), which explains the observed insensitivity to pain following genetic removal or inhibition of Nav1.7.
电压门控钠离子通道 Nav1.7 的功能丧失突变会导致人类先天性无痛症（CIP），这表明 Nav1.7 对于疼痛感知至关重要。然而，Nav1.7 的缺失如何导致对疼痛不敏感的机制尚不完全清楚。有人提出，Nav1.7 的缺失会诱导内啡肽的过度表达，内啡肽是一种内源性阿片受体激动剂，导致阿片类药物依赖的镇痛作用。通过行为药理学和单细胞 RNA-seq 分析，我们发现只有在涉及低阈值触摸检测的感觉神经元子类 cLTMR 神经元中才会发生内啡肽的过度表达，而这种过度表达在 Nav1.7 基因缺失后观察到的镇痛中不起作用。此外，我们通过激光散斑对比成像（LSCI）和体内电生理学证明，Nav1.7 的功能对于 C 纤维动作电位（AP）的起始是必需的，这解释了 Nav1.7 基因缺失或抑制后观察到的疼痛不敏感现象。
