Nassar Mohammed A, Stirling L Caroline, Forlani Greta, Baker Mark D, Matthews Elizabeth A, Dickenson Anthony H, Wood John N
Molecular Nociception Group, Biology Department, and Pharmacology Department, University College London, Gower Street, London WC1E 6BT, United Kingdom.
Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12706-11. doi: 10.1073/pnas.0404915101. Epub 2004 Aug 16.
Nine voltage-gated sodium channels are expressed in complex patterns in mammalian nerve and muscle. Three channels, Na(v)1.7, Na(v)1.8, and Na(v)1.9, are expressed selectively in peripheral damage-sensing neurons. Because there are no selective blockers of these channels, we used gene ablation in mice to examine the function of Na(v)1.7 (PN1) in pain pathways. A global Na(v)1.7-null mutant was found to die shortly after birth. We therefore used the Cre-loxP system to generate nociceptor-specific knockouts. Na(v)1.8 is only expressed in peripheral, mainly nociceptive, sensory neurons. We knocked Cre recombinase into the Na(v)1.8 locus to generate heterozygous mice expressing Cre recombinase in Na(v)1.8-positive sensory neurons. Crossing these animals with mice where Na(v)1.7 exons 14 and 15 were flanked by loxP sites produced nociceptor-specific knockout mice that were viable and apparently normal. These animals showed increased mechanical and thermal pain thresholds. Remarkably, all inflammatory pain responses evoked by a range of stimuli, such as formalin, carrageenan, complete Freund's adjuvant, or nerve growth factor, were reduced or abolished. A congenital pain syndrome in humans recently has been mapped to the Na(v)1.7 gene, SCN9A. Dominant Na(v)1.7 mutations lead to edema, redness, warmth, and bilateral pain in human erythermalgia patients, confirming an important role for Na(v)1.7 in inflammatory pain. Nociceptor-specific gene ablation should prove useful in understanding the role of other broadly expressed genes in pain pathways.
九种电压门控钠通道在哺乳动物的神经和肌肉中以复杂的模式表达。三种通道，即Na(v)1.7、Na(v)1.8和Na(v)1.9，在外周损伤感知神经元中选择性表达。由于没有这些通道的选择性阻滞剂，我们利用小鼠基因敲除技术来研究Na(v)1.7（PN1）在疼痛通路中的功能。结果发现，完全缺失Na(v)1.7的突变小鼠在出生后不久就死亡。因此，我们使用Cre-loxP系统来产生伤害感受器特异性敲除小鼠。Na(v)1.8仅在外周主要为伤害性的感觉神经元中表达。我们将Cre重组酶敲入Na(v)1.8基因座，以产生在Na(v)1.8阳性感觉神经元中表达Cre重组酶的杂合小鼠。将这些动物与Na(v)1.7基因的第14和15外显子两侧带有loxP位点的小鼠杂交，产生了存活且外观正常的伤害感受器特异性敲除小鼠。这些动物的机械性和热痛阈值升高。值得注意的是，由多种刺激物（如福尔马林、角叉菜胶、完全弗氏佐剂或神经生长因子）诱发的所有炎症性疼痛反应均减弱或消失。最近，人类的一种先天性疼痛综合征已被定位到Na(v)1.7基因SCN9A。显性Na(v)1.7突变导致人类红斑性肢痛症患者出现水肿、发红、发热和双侧疼痛，证实了Na(v)1.7在炎症性疼痛中起重要作用。伤害感受器特异性基因敲除在理解其他广泛表达的基因在疼痛通路中的作用方面应该会被证明是有用的。
