Differential effects of cannabinoid receptor agonists on regional brain activity using pharmacological MRI
Differential effects of cannabinoid receptor agonists on regional brain activity using pharmacological MRI
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DOI：
10.1038/sj.bjp.0707506
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发表时间：
2008-01-01
影响因子：
7.3
通讯作者：
Fox, G. B.
中科院分区：
文献类型：
--
作者：
Chin, C-L;Tovcimak, A. E.;Fox, G. B.
背景和目的：大麻素CB 1和/或CB 2受体的激活介导了广泛的临床前疼痛模型的镇痛作用。CB 2受体的选择性激活可以产生镇痛，而没有与CB 1受体的调节相关的不期望的精神副作用。为了解决在体内的选择性，我们描述了非侵入性，非电离，功能性数据，区分CB 1从CB 2受体神经活动使用药理MRI（phMRI）在清醒的大鼠。实验方法：使用高场（7 T）MRI扫描仪，我们检测并定量了非选择性CB 1/CB 2（A-834735）和选择性CB 2（AM 1241）激动剂对清醒大鼠神经活动的影响。使用选择性CB 1（利莫那班）或CB 2（AM 630）拮抗剂测定药理学特异性。行为研究，血浆和大脑的曝光被用作基准活动invivo.Key结果：非选择性CB 1/CB 2激动剂产生了剂量相关的，区域特异性激活的大脑结构，同意与出版的放射自显影CB 1受体密度结合地图。预处理与CB 1拮抗剂，但不与CB 2拮抗剂，取消这些激活模式，表明由CB 1受体单独介导的效果。与此相反，没有显着的变化，大脑活动被发现与相关剂量的CB 2选择性agonist.Conclusion和影响：这些结果提供了第一个明确的证据，量化在体内的功能选择性之间的CB 1和CB 2受体使用phMRI。此外，由于CB 2受体在大脑中的存在仍然存在争议，我们的数据表明，如果CB 2受体表达，它们在正常生理条件下没有功能。
Background and purpose: Activation of cannabinoid CB1 and/or CB2 receptors mediates analgesic effects across a broad spectrum of preclinical pain models. Selective activation of CB2 receptors may produce analgesia without the undesirable psychotropic side effects associated with modulation of CB1 receptors. To address selectivity in vivo, we describe non-invasive, non-ionizing, functional data that distinguish CB1 from CB2 receptor neural activity using pharmacological MRI (phMRI) in awake rats.Experimental approach: Using a high field (7 T) MRI scanner, we examined and quantified the effects of non-selective CB1/CB2 (A-834735) and selective CB2 (AM1241) agonists on neural activity in awake rats. Pharmacological specificity was determined using selective CB1 (rimonabant) or CB2 (AM630) antagonists. Behavioural studies, plasma and brain exposures were used as benchmarks for activity in vivo.Key results: The non-selective CB1/CB2 agonist produced a dose-related, region-specific activation of brain structures that agrees well with published autoradiographic CB1 receptor density binding maps. Pretreatment with a CB1 antagonist but not with a CB2 antagonist, abolished these activation patterns, suggesting an effect mediated by CB1 receptors alone. In contrast, no significant changes in brain activity were found with relevant doses of the CB2 selective agonist.Conclusion and implications: These results provide the first clear evidence for quantifying in vivo functional selectivity between CB1 and CB2 receptors using phMRI. Further, as the presence of CB2 receptors in the brain remains controversial, our data suggest that if CB2 receptors are expressed, they are not functional under normal physiological conditions.