BRAIN CANNABINOID RECEPTOR SIGNALING AND PHARMACOLOGY

描述：（申请人摘要） 大麻（Cannabis sativa）具有悠久的药用历史， 和娱乐目的。 自从克隆中枢神经系统以来 大麻素受体及其在特定脑区的定位;问题 关于这种受体在正常脑功能中的作用的研究已经出现。 由于对大麻素受体在正常组织中的作用知之甚少， 我们的长期目标是了解基本的细胞生物学 这种受体的想法，这可能有助于我们了解的作用， 大麻素受体在学习和记忆，感觉知觉 包括疼痛食欲和恶心 我们研究的第一个目的 是为了研究大鼠大脑中大麻素受体的功能， 使用新的神经元表达的细胞电生理水平 系统 初步实验表明，分离的成年大鼠 注射cRNA的交感神经节神经元体外转录 从大鼠脑大麻素受体cDNA表达功能性大麻素 18小时内接收。 表达既稳健又可靠。 的 异源表达的大鼠脑大麻素受体抑制 电压依赖性钙通道活性。 这是第一次演示 克隆的大鼠脑大麻素的表达和功能偶联 成年神经元中的受体。 表达一种认同的能力 正常成年哺乳动物神经元中的大麻素受体和受体突变体 将有助于识别离子通道靶点、细胞通路和 大麻素受体的结构/功能研究。 的第二个目的 我们提出的研究是为了验证大麻素 受体是自发活性的，可以在缺乏G蛋白的情况下与G蛋白偶联。 内源性配体。 自发性大麻素受体的作用 正常大脑功能的活动或药物滥用行为完全 未知 我们的实验将解决的功能后果， 克隆和天然大麻素受体的自发活性。 的 我们研究的第三个目的是测试功能耦合和自发性 大麻素受体在其天然环境中的活性。 原生 中枢和外周神经系统神经元中的大麻素受体 将使用细胞电生理技术进行研究。 如果 大麻素受体在其天然的 环境，这种活动将改变正常的生理和 拮抗剂信号传导的结果。 一种自发活性的大麻素 受体将具有重要的功能后果和负面影响 拮抗剂可能具有潜在的治疗益处。

DESCRIPTION: (Applicant's Abstract) Marijuana (Cannabis sativa) has had long history of use for both medicinal and recreational purposes. Since the cloning of a central nervous system cannabinoid receptor and its localization in specific brain areas; questions concerning the role of this receptor in normal brain function have arisen. Since little is known about the role of the cannabinoid receptor in normal brain function, our long term goals are to understand the basic cell biology of this receptor with the idea that this may help us understand the role of the cannabinoid receptor in learning and memory, sensory perception including pain, appetite and nausea. The first aim of our proposed research is to investigate the function of the rat brain cannabinoid receptor at the cellular electrophysiological level using a novel neuronal expression system. Preliminary experiments demonstrate that dissociated adult rat sympathetic ganglion neurons microinjected with cRNA in vitro transcribed from rat brain cannabinoid receptor cDNA express a functional cannabinoid receptor within 18 hours. Expression is both robust and reliable. The heterologously expressed rat brain cannabinoid receptor inhibits voltage-dependent calcium channel activity. This is the first demonstration of expression and functional coupling of the cloned rat brain cannabinoid receptor in an adult neuron. The ability to express an identified cannabinoid receptor and receptor mutants in normal adult mammalian neurons will facilitate identification of ion channel targets, cellular pathways and structure/function studies of the cannabinoid receptor. The second aim of our proposed research is to test the hypothesis that the cannabinoid receptor is spontaneously active and can couple to G proteins in the absence of endogenous ligands. The role of spontaneous cannabinoid receptor activity in normal brain function or drug abuse behavior is completely unknown. Our experiments will address the functional consequences of spontaneous activity of both cloned and native cannabinoid receptors. The third aim of our research is to test the functional coupling and spontaneous activity of the cannabinoid receptors in their native environment. Native cannabinoid receptors in both central and peripheral nervous system neurons will be studied using cellular electrophysiological techniques. If the cannabinoid receptor is spontaneously active in its native environment, this activity will change both normal physiology and the outcome of antagonist signaling. A spontaneously active cannabinoid receptor will have important functional consequences and negative antagonists could have potential therapeutic benefits.