Morgan Nicola H, Stanford Ian M, Woodhall Gavin L
Biomedical Sciences, School of Life & Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK.
Neuropharmacology. 2009 Sep;57(4):356-68. doi: 10.1016/j.neuropharm.2009.07.017. Epub 2009 Jul 16.
To date, it has been thought that cannabinoid receptors in CNS are primarily of the CB1R subtype, with CB2R expressed only in glia and peripheral tissues. However, evidence for the expression of CB2 type cannabinoid receptors at neuronal sites in the CNS is building through anatomical localization of receptors and mRNA in neurons and behavioural studies of central effects of CB2R agonists. In the medial entorhinal area of the rat, we found that blockade of CB1R did not occlude suppression of GABAergic inhibition by the non-specific endogenous cannabinoid 2-AG, suggesting that CB1R could not account fully for the effects of 2-AG. Suppression could be mimicked using the CB2R agonist JWH-133 and reversed by the CB2R inverse agonist AM-630, indicating the presence of functional CB2R. When we reversed the order of drug application AM-630 blocked the effects of the CB2R agonist JWH-133, but not the CB1R inverse agonist LY320135. JTE-907, a CB2R inverse agonist structurally unrelated to AM-630 elicited increased GABAergic neurotransmission at picomolar concentrations. Analysis of mIPSCs revealed that CB2R effects were restricted to action potential dependent, but not action potential independent GABA release. These data provide pharmacological evidence for functional CB2R at CNS synapses.
迄今为止，人们一直认为中枢神经系统（CNS）中的大麻素受体主要是CB1R亚型，而CB2R仅在神经胶质细胞和外周组织中表达。然而，通过对神经元中受体和mRNA的解剖定位以及CB2R激动剂中枢效应的行为学研究，越来越多的证据表明CNS中神经元部位存在CB2型大麻素受体。在大鼠的内侧内嗅区，我们发现阻断CB1R并不能消除非特异性内源性大麻素2-AG对GABA能抑制的抑制作用，这表明CB1R不能完全解释2-AG的作用。使用CB2R激动剂JWH-133可模拟这种抑制作用，而CB2R反向激动剂AM-630可逆转这种作用，这表明存在功能性CB2R。当我们颠倒药物应用顺序时，AM-630可阻断CB2R激动剂JWH-133的作用，但不能阻断CB1R反向激动剂LY320135的作用。JTE-907是一种与AM-630结构无关的CB2R反向激动剂，在皮摩尔浓度下可引起GABA能神经传递增加。对微小抑制性突触后电流（mIPSCs）的分析表明，CB2R的作用仅限于依赖动作电位的GABA释放，而不涉及不依赖动作电位的GABA释放。这些数据为CNS突触处功能性CB2R提供了药理学证据。
