Sodium channel inhibition by anandamide and synthetic cannabimimetics in brain
Sodium channel inhibition by anandamide and synthetic cannabimimetics in brain
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DOI：
10.1016/s0006-8993(03)02808-7
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发表时间：
2003-07-18
期刊：
影响因子：
2.9
通讯作者：
Lees, G
中科院分区：
文献类型：
--
作者：
Nicholson, RA;Liao, C;Lees, G
大麻素是内源性大麻素的重要成员，内源性大麻素是一组影响神经元兴奋性的可扩散脂质分子。在这种情况下，已知内源性大麻素通过大麻素（CB 1）受体刺激和第二信使途径激活或直接作用来调节某些突触前Ca 2+和K+通道。我们研究了电压敏感性钠通道的敏感性anandamide和其他cannibimimetics使用生化和电生理方法。在此我们报道了花生四烯酸、AM 404和WIN 55，212 -2抑制突触神经体的藜芦碱依赖性去极化（IC（50）s分别为21.8、9.3和21.1 μ M）和从纯化的突触体中释放L-谷氨酸和GABA的藜芦碱依赖性[IC（50）s：花生四烯酸为5.1 μ M（L-glu）和16.5 μ M（GABA）; AM 404为1.6 μ M（L-glu）和3.3 μ M（GABA），WIN 55为12.2（L-glu）和14.4 μ M（GABA），212 -2]。[H-3]蟾毒素A 20-α-苯甲酸酯与电压敏感性钠通道的结合也被低至中等微摩尔浓度的花生四烯酸、AM 404和WIN 55，212 -2抑制。此外，发现anandamide（10 μ M）、AM 404（10 μ M）和WIN 55，212 -2（1 μ M）显著阻断皮质神经元中TTX敏感的持续重复放电而不改变初级尖峰，这与状态依赖性机制一致。我们证明的对电压敏感性钠通道的抑制作用都不会被有效的CBI拮抗剂AM 251（1-2 μ M）减弱。花生四烯酸酰胺的作用是可逆的，其作用通过抑制脂肪酸酰胺水解酶而增强。我们建议，电压敏感性钠通道可能参与一个新的信号通路，涉及花生四烯酸。这种机制有可能通过抑制神经元支持动作电位的能力和减少兴奋性和抑制性递质的诱发释放来抑制脑中的突触传递。(C)2003 Elsevier Science B. V.保留所有权利。
Anandamide is a prominent member of the endocannabinoids, a group of diffusible lipid molecules which influences neuronal excitability. In this context, endocannabinoids are known to modulate certain presynaptic Ca2+ and K+ channels, either through cannabinoid (CB1) receptor stimulation and second messenger pathway activation or by direct action. We investigated the susceptibility of voltage-sensitive sodium channels to anandamide and other cannibimimetics using both biochemical and electrophysiological approaches. Here we report that anandamide, AM 404 and WIN 55,212-2 inhibit veratridine-dependent depolarization of synaptoneurosomes (IC(50)s, respectively 21.8, 9.3 and 21.1 muM) and veratridine-dependent release Of L-glutamic acid and GABA from purified synaptosomes [IC(50)s: 5.1 muM (L-glu) and 16.5 muM (GABA) for anandamide; 1.6 muM (L-glu) and 3.3 muM (GABA) for AM 404, and 12.2 (L-glu) and 14.4 muM (GABA) for WIN 55,212-2]. The binding of [H-3]batrachotoxinin A 20-alpha-benzoate to voltage-sensitive sodium channels was also inhibited by low to mid micromolar concentrations of anandamide, AM 404 and WIN 55,212-2. In addition, anandamide (10 muM), AM 404 (10 muM) and WIN 55,212-2 (1 muM) were found to markedly block TTX-sensitive sustained repetitive firing in cortical neurones without altering primary spikes, consistent with a state-dependent mechanism. None of the inhibitory effects we demonstrate on voltage-sensitive sodium channels are attenuated by the potent CBI antagonist AM 251 (1-2 muM). Anandamide's action is reversible and its effects are enhanced by fatty acid amidohydrolase inhibition. We propose that voltage-sensitive sodium channels may participate in a novel signaling pathway involving anandamide. This mechanism has potential to depress synaptic transmission in brain by damping neuronal capacity to support action potentials and reducing evoked release of both excitatory and inhibitory transmitters. (C) 2003 Elsevier Science B.V. All rights reserved.