Department of Anesthesiology, Central Japan International Medical Center, Minokamo 505-8510, Gifu, Japan.
Department of Dental Basic Education, School of Dentistry, Asahi University, Mizuho 501-0296, Gifu, Japan.
Int J Mol Sci. 2022 Apr 2;23(7):3971. doi: 10.3390/ijms23073971.
Although the pharmacological activity of capsaicin has been explained by its specific binding to transient receptor potential vanilloid type 1, the amphiphilic structure of capsaicin may enable it to act on lipid bilayers. From a mechanistic point of view, we investigated whether capsaicin and its antagonist capsazepine interact with biomimetic membranes, and how capsazepine influences the membrane effect of capsaicin. Liposomal phospholipid membranes and neuro-mimetic membranes were prepared with 1,2-dipalmitoylphosphatidylcholine and with 1-palmitoyl-2-oleoylphosphatidylcholine and sphingomyelin plus cholesterol, respectively. These membrane preparations were subjected to reactions with capsaicin and capsazepine at 0.5-250 μM, followed by measuring fluorescence polarization to determine the membrane interactivity to modify the fluidity of membranes. Both compounds acted on 1,2-dipalmitoylphosphatidylcholine bilayers and changed membrane fluidity. Capsaicin concentration-dependently interacted with neuro-mimetic membranes to increase their fluidity at low micromolar concentrations, whereas capsazepine inversely decreased the membrane fluidity. When used in combination, capsazepine inhibited the effect of capsaicin on neuro-mimetic membranes. In addition to the direct action on transmembrane ion channels, capsaicin and capsazepine share membrane interactivity, but capsazepine is likely to competitively antagonize capsaicin's interaction with neuro-mimetic membranes at pharmacokinetically-relevant concentrations. The structure-specific membrane interactivity may be partly responsible for the analgesic effect of capsaicin.
虽然辣椒素的药理学活性可以通过其与瞬时受体电位香草素 1 型的特异性结合来解释，但辣椒素的两亲性结构可能使其能够作用于脂质双层。从机制的角度来看，我们研究了辣椒素及其拮抗剂 Capsazepine 是否与仿生膜相互作用，以及 Capsazepine 如何影响辣椒素对膜的作用。分别用 1,2-二棕榈酰磷脂酰胆碱和 1-棕榈酰-2-油酰磷脂酰胆碱与神经拟态膜和鞘磷脂加胆固醇制备脂质体磷脂膜。将这些膜制剂与辣椒素和 Capsazepine 在 0.5-250 μM 下进行反应，然后通过测量荧光偏振来确定与膜相互作用以改变膜流动性。这两种化合物都作用于 1,2-二棕榈酰磷脂酰胆碱双层并改变膜流动性。辣椒素浓度依赖性地与神经拟态膜相互作用，在低微摩尔浓度下增加其流动性，而 Capsazepine 则相反地降低膜流动性。当联合使用时，Capsazepine 抑制了 Capsazepine 对神经拟态膜的作用。除了对跨膜离子通道的直接作用外，辣椒素和 Capsazepine 具有膜相互作用，但 Capsazepine 可能在药代动力学相关浓度下竞争性拮抗 Capsazepine 与神经拟态膜的相互作用。结构特异性的膜相互作用可能部分解释了辣椒素的镇痛作用。
