Sheets Patrick L, Gerner Peter, Wang Chi-Fei, Wang Sho-Ya, Wang Ging Kuo, Cummins Theodore R
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
J Neurophysiol. 2006 Oct;96(4):1848-59. doi: 10.1152/jn.00354.2006. Epub 2006 Jun 28.
The calmodulin (CaM) inhibitor trifluoperazine (TFP) can produce analgesia when given intrathecally to rats; however, the mechanism is not known. We asked whether TFP could modulate the Na(v)1.7 sodium channel, which is highly expressed in the peripheral nervous system and plays an important role in nociception. We show that 500 nM and 2 muM TFP induce major decreases in Na(v)1.7 and Na(v)1.4 current amplitudes and that 2 muM TFP causes hyperpolarizing shifts in the steady-state inactivation of Na(v)1.7 and Na(v)1.4. CaM can bind to the C-termini of voltage-gated sodium channels and modulate their functional properties; therefore we investigated if TFP modulation of sodium channels was due to CaM inhibition. However, the TFP inhibition was not replicated by whole cell dialysis of a calmodulin inhibitory peptide, indicating that major effects of TFP do not involve a disruption of CaM-channel interactions. Rather, our data show that TFP inhibition is state dependent and that the majority of the TFP inhibition depends on specific amino-acid residues in the local anesthetic receptor site in sodium channels. TFP was also effective in vivo in causing motor and sensory blockade after subfascial injection to the rat sciatic nerve. The state-dependent block of Na(v)1.7 channels with nanomolar concentrations of TFP raises the possibility that TFP, or TFP analogues, might be useful for regional anesthesia and pain management and could be more potent than traditional local anesthetics.
钙调蛋白（CaM）抑制剂三氟拉嗪（TFP）鞘内注射给大鼠时可产生镇痛作用；然而，其机制尚不清楚。我们研究了TFP是否能调节Na(v)1.7钠通道，该通道在外周神经系统中高度表达且在伤害感受中起重要作用。我们发现500 nM和2 μM的TFP可使Na(v)1.7和Na(v)1.4电流幅度大幅降低，且2 μM的TFP可使Na(v)1.7和Na(v)1.4的稳态失活发生超极化偏移。CaM可与电压门控钠通道的C末端结合并调节其功能特性；因此我们研究了TFP对钠通道的调节是否归因于CaM抑制。然而，钙调蛋白抑制肽的全细胞透析并未重现TFP的抑制作用，这表明TFP的主要作用并不涉及CaM与通道相互作用的破坏。相反，我们的数据表明TFP的抑制是状态依赖性的，且TFP的大部分抑制作用取决于钠通道局部麻醉药受体位点中的特定氨基酸残基。TFP在大鼠坐骨神经筋膜下注射后在体内引起运动和感觉阻滞方面也有效。纳摩尔浓度的TFP对Na(v)1.7通道的状态依赖性阻滞增加了TFP或TFP类似物可能对区域麻醉和疼痛管理有用且可能比传统局部麻醉药更有效的可能性。
