N-oleoyldopamine, a novel endogenous capsaicin-like lipid that produces hyperalgesia
N-oleoyldopamine, a novel endogenous capsaicin-like lipid that produces hyperalgesia
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DOI：
10.1074/jbc.m211231200
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发表时间：
2003-04-18
影响因子：
4.8
通讯作者：
Walker, JM
中科院分区：
文献类型：
--
作者：
Chu, CJ;Huang, SM;Walker, JM
N-花生四烯酸多巴胺（NADA）是近年来发现的一种香草素1型受体（VR 1）的内源性配体。进一步分析从中分离NADA的牛纹状体提取物表明存在分子量对应于N-油酰多巴胺（OLDA）、N-棕榈酰多巴胺（PALDA）和N-硬脂酰多巴胺（STEARDA）的物质。四极杆飞行时间质谱分析牛纹状体提取物显示存在的OLDA，PALDA，STEARDA作为内源性化合物在哺乳动物大脑。PALDA和STEARDA未能影响VR 1转染的人胚肾（HEK）293细胞中的钙内流或从辐射热源中拔爪延迟，并且没有自发疼痛行为的证据。相比之下，OLDA诱导钙内流（EC 50 = 36 nM），减少了从辐射热源的爪撤回的潜伏期，以剂量依赖性的方式（EC 50 = 0.72 μ g），并产生伤害反应行为。这些作用被VR 1的联合给药阻断。拮抗剂碘-树脂毒素（10 nm用于HEK细胞，1 μ g/50穆尔用于疼痛行为）。这些发现表明大脑中存在一种内源性化合物，其化学结构和对VR 1的活性与辣椒素和NADA相似。与NADA不同，OLDA只是大鼠CB 1受体的弱配体;但与NADA一样，它被花生四烯酸膜转运蛋白识别，同时是脂肪酸酰胺水解酶的不良底物。六个额外的合成和潜在的内源性N-酰基多巴胺的活性分析表明，需要一个长的不饱和脂肪酸链与VR 1受体的最佳功能相互作用。
N-Arachidonoyldopamine (NADA) was recently identified as an endogenous ligand for the vanilloid type 1 receptor (VR1). Further analysis of the bovine striatal extract from which NADA was isolated indicated the existence of substances corresponding in molecular mass to N-oleoyldopamine (OLDA), N-palmitoyldopamine (PALDA), and N-stearoyldopamine (STEARDA). Quadrupole time-of-flight mass spectrometric analysis of bovine striatal extracts revealed the existence of OLDA, PALDA, and STEARDA as endogenous compounds in the mammalian brain. PALDA and STEARDA failed to affect calcium influx in VR1-transfected human embryonic kidney (HEK) 293 cells or paw withdrawal latencies from a radiant heat source, and there was no evidence of spontaneous pain behavior. By contrast, OLDA induced calcium influx (EC50 = 36 nM), reduced the latency of paw withdrawal from a radiant heat source in a dose-dependent manner (EC50 = 0.72 mug), and produced nocifensive behavior. These effects were blocked by co-administration of the VR1. antagonist iodo-resiniferatoxin (10 nm for HEK cells and 1 mug/50 mul for pain behavior). These findings demonstrate the existence of an endogenous compound in the brain that is similar to capsaicin and NADA in its chemical structure and activity on VR1. Unlike NADA, OLDA was only a weak ligand for rat CB1 receptors; but like NADA, it was recognized by the anandamide membrane transporter while being a poor substrate for fatty-acid amide hydrolase. Analysis of the activity of six additional synthetic and potentially endogenous N-acyldopamine indicated the requirement of a long unsaturated fatty acid chain for an optimal functional interaction with VR1 receptors.