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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >CB_2 cannabinoid receptor antagonist SR144528 decreases mu-opioid receptor expression and activation in mouse brainstem: role of CB_2 receptor in pain.
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CB_2 cannabinoid receptor antagonist SR144528 decreases mu-opioid receptor expression and activation in mouse brainstem: role of CB_2 receptor in pain.

机译：CB_2大麻素受体拮抗剂SR144528降低了鼠脑干中μ阿片受体的表达和激活：CB_2受体在疼痛中的作用。

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Formerly considered as an exclusively peripheral receptor, it is now accepted that CB(2) cannabinoid receptor is also present in limited amounts and distinct locations in the brain of several animal species, including mice. However, the possible roles of CB(2) receptors in the brain need to be clarified. The aim of our work was to study the mu-opioid receptor (MOR) mRNA expression level and functional activity after acute in vivo and in vitro treatments with the endocannabinoid noladin ether (NE) and with the CB(2) receptor antagonist SR144528 in brainstem of mice deficient in either CB(1) or CB(2) receptors. This study is based on our previous observations that noladin ether (NE) produces decrease in the activity of MOR in forebrain and this attenuation can be antagonized by the CB(2) cannabinoid antagonist SR144528, suggesting a CB(2) receptor mediated effect. We used quantitative real-time PCR to examine the changes of MOR mRNA levels, [(35)S]GTPgammaS binding assay to analyze the capability of mu-opioid agonist DAMGO to activate G-proteins and competition binding assays to directly measure the ligand binding to MOR in mice brainstem. After acute NE administration no significant changes were observed on MOR signaling. Nevertheless pretreatment of mice with SR144528 prior to the administration of NE significantly decreased MOR signaling suggesting the involvement of SR144528 in mediating the effect of MOR. mRNA expression of MORs significantly decreased both in CB(1) wild-type and CB(1) knockout mice after a single injection of SR144528 at 0.1mg/kg when compared to the vehicle treated controls. Consequently, MOR-mediated signaling was attenuated after acute in vivo treatment with SR144528 in both CB(1) wild-type and CB(1) knockout mice. In vitro addition of 1microM SR144528 caused a decrease in the maximal stimulation of DAMGO in [(35)S]GTPgammaS binding assays in CB(2) wild-type brainstem membranes whereas no significant changes were observed in CB(2) receptor knockouts. Radioligand binding competition studies showed that the noticed effect of SR144528 on MOR signaling is not mediated through MORs. Our data demonstrate that the SR144528 caused pronounced decrease in the activity of MOR is mediated via CB(2) cannabinoid receptors.
机译：CB（2）大麻素受体以前被认为是排他性的外周受体，现在已被接受以有限的数量存在于包括老鼠在内的几种动物的大脑中，且位置不同。但是，CB（2）受体在大脑中的可能作用需要弄清楚。我们的工作目的是研究脑干内源性大麻素Noladin醚（NE）和CB（2）受体拮抗剂SR144528在急性和体内和体外治疗后的μ阿片受体（MOR）mRNA表达水平和功能活性。缺乏CB（1）或CB（2）受体的小鼠。这项研究是基于我们以前的观察结果，诺拉丁醚（NE）降低了前脑中MOR的活性，这种衰减可以被CB（2）大麻素拮抗剂SR144528拮抗，表明CB（2）受体介导的作用。我们使用定量实时PCR来检测MOR mRNA水平的变化，[（35）S] GTPgammaS结合测定分析μ阿片激动剂DAMGO激活G蛋白的能力，竞争结合测定直接测量配体结合对小鼠脑干中的MOR。急性NE给药后，在MOR信号传导上未观察到显着变化。然而，在施用NE之前用SR144528对小鼠的预处理显着降低了MOR信号传导，表明SR144528参与介导MOR的作用。与媒介物处理的对照组相比，单次注射0.1mg / kg SR144528后，CB（1）野生型和CB（1）敲除小鼠中MOR的mRNA表达均显着降低。因此，在CB（1）野生型和CB（1）敲除小鼠中，用SR144528进行急性体内治疗后，MOR介导的信号减弱。 1microM SR144528的体外添加导致CB（2）野生型脑干膜[（35）S] GTPgammaS结合测定中DAMGO的最大刺激降低，而CB（2）受体敲除未观察到显着变化。放射性配体结合竞争研究表明，SR144528对MOR信号的显著作用不是通过MOR介导的。我们的数据表明，SR144528引起的MOR活性明显下降是通过CB（2）大麻素受体介导的。

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