Examination of the contribution of Nav1.7 to axonal propagation in nociceptors
Examination of the contribution of Nav1.7 to axonal propagation in nociceptors
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检查 Nav1.7 对伤害感受器轴突传播的贡献
DOI：
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
S. McMahon
中科院分区：
文献类型：
--
作者：
G. Goodwin;S. McMurray;E. Stevens;Franziska Denk;S. McMahon
Nav1.7是治疗疼痛的有前景的药物靶点，因为带有Nav1.7功能丧失突变的人对疼痛不敏感，也没有其他严重的神经缺陷。然而，目前外周受限的Nav1.7抑制剂在临床疼痛试验中表现不佳，这可能反映出对Nav1.7在伤害性信息传递中的功能缺乏了解。尽管已有大量研究报道Nav1.7在外周转导中具有温和的作用，但Nav1.7在伤害性感受器中对轴突传播的确切贡献尚不清楚，特别是对于支配深层结构的传入。在这项研究中，我们利用小鼠L4的在体电生理和钙成像记录，研究了Nav1.7对使用钠通道阻滞剂的伤害性感受器轴突传播的贡献。用钠通道阻滞剂河豚毒素(1-10μM)阻断NAV1.7和其他河豚毒素-S沿坐骨神经的钠通道，我们首先发现，大约2/3个支配皮肤的伤害性神经元被河豚毒素阻断，但支配肌肉的比例较低(45%)。相反，几乎所有的大型A纤维皮肤传入(95%-100%)都被轴突TTX阻断。对TTX抗性皮肤伤害性感受器的特征表明，许多是多模式的(57%)和辣椒素敏感的(57%)。接下来，我们通过将选择性通道阻滞剂PF-05198007(300 Nm-1μM)应用于刺激和记录位置之间的坐骨神经，研究了NA1.7在伤害性神经元轴突传播中的作用。100-300 nM的PF-05198007阻断63%的C纤维感觉神经元的传播，而相似浓度的PF-100不影响快速传导的A纤维神经元的传播。我们得出结论：NA1.7仅在大约2/3rd的伤害性C纤维神经元中对轴突传播有重要贡献，而在支配肌肉的伤害性神经元中比例较低(≤为45%)。
Nav1.7 is a promising drug target for the treatment of pain because individuals with Nav1.7 loss-of-function mutations are insensitive to pain and do not have other serious neurological deficits. However, current peripherally restricted Nav1.7 inhibitors have not performed well in clinical pain trials, which may reflect a lack of understanding of the function of Nav1.7 in the transmission of nociceptive information. Although numerous studies have reported that Nav1.7 has a moderate role in peripheral transduction, the precise contribution of Nav1.7 to axonal propagation in nociceptors is not clearly defined, particularly for afferents innervating deep structures. In this study, we examined the contribution of Nav1.7 to axonal propagation in nociceptors utilising sodium channel blockers in in vivo electrophysiological and calcium imaging recordings from L4 in the mouse. Using the sodium channel blocker TTX (1-10μM) to inhibit Nav1.7 and other TTX-S sodium channels along the sciatic nerve, we first showed that around 2/3rds of nociceptive neurons innervating the skin, but a lower proportion innervating the muscle (45%), are blocked by TTX. In contrast, nearly all large-sized A-fibre cutaneous afferents (95-100%) were blocked by axonal TTX. Characterisation of TTX resistant cutaneous nociceptors revealed that many were polymodal (57%) and capsaicin sensitive (57%). Next, we examined the role of Nav1.7 in axonal propagation in nociceptive neurons by applying the selective channel blocker PF-05198007 (300nM-1μM) to the sciatic nerve between stimulating and recording sites. 100-300nM PF-05198007 blocked propagation in 63% of C-fibre sensory neurons, whereas similar concentrations did not affect propagation in rapidly conducting A-fibre neurons. We conclude that Nav1.7 has an essential contribution to axonal propagation in only around 2/3rds of nociceptive C-fibre neurons, and a lower proportion (≤45%) of nociceptive neurons innervating muscle.
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影响因子：
14.8
作者：
Zimmermann K;Hein A;Hager U;Kaczmarek JS;Turnquist BP;Clapham DE;Reeh PW
通讯作者：
Reeh PW
影响因子：
5
作者：
Zhiling Xiong;Zhiling Xiong;Gary R. Strichartz;Gary R. Strichartz
通讯作者：
Zhiling Xiong;Zhiling Xiong;Gary R. Strichartz;Gary R. Strichartz
DOI：
10.1073/pnas.090034797
发表时间：
2000-05-09
影响因子：
11.1
作者：
Caldwell, JH;Schaller, KL;Levinson, SR
通讯作者：
Levinson, SR
影响因子：
64.8
作者：
Weiss, Jan;Pyrski, Martina;Jacobi, Eric;Bufe, Bernd;Willnecker, Vivienne;Schick, Bernhard;Zizzari, Philippe;Gossage, Samuel J.;Greer, Charles A.;Leinders-Zufall, Trese;Woods, C. Geoffrey;Wood, John N.;Zufall, Frank
通讯作者：
Zufall, Frank
影响因子：
5.3
作者：
Klein, Amanda H.;Vyshnevska, Alina;Ringkamp, Matthias
通讯作者：
Ringkamp, Matthias