Harrison Selena, De Petrocellis Luciano, Trevisani Marcello, Benvenuti Francesca, Bifulco Maurizio, Geppetti Pierangelo, Di Marzo Vincenzo
Dipartimento di Medicina Sperimentale e Clinica, Università di Ferrara, Via Fossato di Mortara 19, Ferrara, Italy.
Eur J Pharmacol. 2003 Aug 15;475(1-3):107-14. doi: 10.1016/s0014-2999(03)02114-9.
A capsaicin-like endogenous ligand of vanilloid (VR1) receptors, N-arachidonoyl-dopamine, was recently identified in bovine and rat nervous tissue, and found to be almost as potent as capsaicin, and 5-10-fold more potent than anandamide, on these receptors, both in isolated cells and in vivo. Here we have investigated if N-arachidonoyl-dopamine also exerts other capsaicin-like effects at VR1 receptors in some isolated organ preparations. N-arachidonoyl-dopamine exerted a potent contractile response of guinea pig isolated bronchi (EC50=12.6 +/- 1.7 microM, Emax=69.2 +/- 2.4% of carbachol Emax), which was blocked by pre-treatment with capsaicin or with the VR1 antagonist capsazepine, as well as by a combination of tachykinin NK1 and NK2 receptor antagonists. In this assay, N-arachidonoyl-dopamine was less and more potent and/or efficacious than capsaicin (EC50=40.0 nM; Emax=93.5%) and anandamide (EC50=15.2 microM, Emax=38.0%), respectively. Unlike capsaicin and anandamide, forskolin or ethanol did not enhance N-arachidonoyl-dopamine effect in this preparation, whereas epithelial denudation resulted in a 2.5-fold increase in potency without affecting the efficacy. N-arachidonoyl-dopamine also contracted the isolated guinea pig urinary bladder, although in this preparation, as well as in the isolated rat urinary bladder, the potency (EC50=3.7 +/- 0.3 and 19.9 +/- 0.1 microM) and/or efficacy (Emax=12.0 +/- 0.1% and 20.7 +/- 0.7% of carbachol Emax) of the compound were significantly lower than those of both capsaicin and anandamide. These data suggest that the extent to which exogenous N-arachidonoyl-dopamine activates VR1 receptor in isolated organs is largely dependent on pharmacodynamics and bioavailability.
一种类辣椒素的香草酸受体（VR1）内源性配体，N-花生四烯酰多巴胺，最近在牛和大鼠神经组织中被鉴定出来，并且发现在分离细胞和体内实验中，它在这些受体上的效力与辣椒素几乎相当，比花生四烯乙醇胺强5至10倍。在此，我们研究了N-花生四烯酰多巴胺在一些分离的器官制剂中是否也会产生其他类辣椒素对VR1受体的作用。N-花生四烯酰多巴胺对豚鼠离体支气管产生了强烈的收缩反应（EC50 = 12.6±1.7微摩尔，Emax = 卡巴胆碱Emax的69.2±2.4%），预先用辣椒素或VR1拮抗剂辣椒平处理，以及用速激肽NK1和NK2受体拮抗剂联合处理均可阻断该反应。在该实验中，N-花生四烯酰多巴胺的效力和/或效能分别低于和高于辣椒素（EC50 = 40.0纳摩尔；Emax = 93.5%）和花生四烯乙醇胺（EC50 = 15.2微摩尔，Emax = 38.0%）。与辣椒素和花生四烯乙醇胺不同，福斯高林或乙醇在此制剂中不会增强N-花生四烯酰多巴胺的作用，而上皮剥脱导致效力增加2.5倍且不影响效能。N-花生四烯酰多巴胺也会使豚鼠离体膀胱收缩，尽管在此制剂以及大鼠离体膀胱中，该化合物的效力（EC50 = 3.7±0.3和19.9±0.1微摩尔）和/或效能（Emax = 卡巴胆碱Emax的12.0±0.1%和20.7±0.7%）均显著低于辣椒素和花生四烯乙醇胺。这些数据表明，外源性N-花生四烯酰多巴胺在离体器官中激活VR1受体的程度在很大程度上取决于药效学和生物利用度。
