Insulin potentiates the response to capsaicin in dorsal root ganglion neurons in vitro and muscle afferents ex vivo in normal healthy rodents.
Insulin potentiates the response to capsaicin in dorsal root ganglion neurons in vitro and muscle afferents ex vivo in normal healthy rodents.
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DOI：
10.1113/jp282740
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发表时间：
2022-03
期刊：
影响因子：
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通讯作者：
Mizuno M
中科院分区：
文献类型：
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作者：
Hori A;Hotta N;Fukazawa A;Estrada JA;Katanosaka K;Mizumura K;Sato J;Ishizawa R;Kim HK;Iwamoto GA;Vongpatanasin W;Mitchell JH;Smith SA;Mizuno M
全身性胰岛素给药引起交感神经兴奋作用，但这些观察结果的机制尚不清楚。我们报道，胰岛素敏感的薄纤维初级传入，以及背根神经节（DRG），使他们，机械刺激的反应。然而，关于胰岛素对化学刺激的初级神经元反应的影响知之甚少。TRPV 1的激动剂是辣椒素（CAP），其在化学敏感的代谢受体和/或伤害感受器上广泛表达。本研究的目的是确定胰岛素对正常健康啮齿类动物的小DRG神经元中CAP激活电流和细纤维肌传入中CAP诱导的动作电位的影响。此外，我们研究了胰岛素是否增强交感神经活动（SNA）对CAP的反应。在离体培养的小鼠DRG神经元的全细胞膜片钳记录中，CAP激活电流从应用胰岛素（n=13）前到应用胰岛素（n= 14）后的倍数变化显著（P<0.05）高于赋形剂对照（n=14）。在离体单纤维记录实验中观察到与载体对照相比胰岛素增强CAP诱导的动作电位类似的结果（每组n=9，P<0.05）。此外，用GSK 1838705阻断胰岛素受体显著抑制了胰岛素诱导的CAP激活电流的增加（n=13）以及CAP诱导的动作电位的响应幅度（n=9）。同样地，肌肉内注射胰岛素（n=8）后肾SNA对CAP的反应显著（P<0.05）大于载体（n=9）。研究结果表明，胰岛素在DRG和肌肉组织水平上增强TRPV 1对CAP的反应性，可能有助于在体育锻炼等活动中增强交感神经兴奋。胰岛素诱导的交感神经活动的增强通过敏化小背根神经节（DRG）神经元和细纤维肌肉传入的瞬时受体电位香草酸1（TRPV 1）。胰岛素增加神经放电响应辣椒素曝光，TRPV 1激动剂，在薄纤维传入水平的DRG在体外和骨骼肌轴突终末离体通过敏化TRPV 1。此外，体内研究表明，肌内注射胰岛素增强交感神经活动和血压对动脉内注射辣椒素的反应。这些发现表明，胰岛素诱导的TRPV 1敏化可能有助于增强交感神经兴奋的活动，如体育锻炼。在BioRender中进行设计。
Systemic insulin administration evokes sympathoexcitatory actions but the mechanisms underlying these observations are unknown. We reported that insulin sensitizes the response of thin-fibre primary afferents, as well as the dorsal root ganglion (DRG) that subserve them, to mechanical stimuli. However, little is known about the effects of insulin on primary neuronal responses to chemical stimuli. TRPV1, whose agonist is capsaicin (CAP), is widely expressed on chemically-sensitive metaboreceptors and/or nociceptors. The aim of this investigation was to determine the effects of insulin on CAP-activated currents in small DRG neurons and CAP-induced action potentials in thin-fibre muscle afferents of normal healthy rodents. Additionally, we investigated whether insulin potentiates sympathetic nerve activity (SNA) responses to CAP. In whole cell patch-clamp recordings from cultured mice DRG neurons in vitro, the fold change in CAP-activated current from pre- to post-application of insulin (n=13) was significantly (P<0.05) higher than those with a vehicle control (n=14). Similar results were observed in single-fibre recording experiments ex vivo as insulin potentiated CAP-induced action potentials compared to vehicle controls (n=9 per group, P<0.05). Furthermore, insulin receptor blockade with GSK1838705, significantly suppressed the insulin-induced augmentation in CAP-activated currents (n=13) as well as the response magnitude of CAP-induced action potentials (n=9). Likewise, the renal SNA response to CAP after intramuscular injection of insulin (n=8) was significantly (P<0.05) greater compared to vehicle (n=9). The findings suggest that insulin potentiates TRPV1 responsiveness to CAP at the DRG and muscle tissue levels, possibly contributing to the augmentation in sympathoexcitation during activities such as physical exercise. Insulin-induced enhancement of sympathetic nerve activity via sensitization of transient receptor potential vanilloid 1 (TRPV1) in small dorsal root ganglion (DRG) neurons and thin-fibre muscle afferents. Insulin increases neural discharge in response to capsaicin exposure, a TRPV1 agonist, in thin-fiber afferents at the level of the DRG in vitro and the skeletal muscle axon terminal ex vivo via sensitization of TRPV1. Further, in vivo studies demonstrate that intramuscular injection of insulin augments sympathetic nerve activity and blood pressure responses to intra-arterial injection of capsaicin. These findings suggest that insulin-induced sensitization of TRPV1 may contribute to the augmentation in sympathoexcitation during activities such as physical exercise. Design made in BioRender.