ENDOGENOUS CANNABINOIDS AND BRAIN/IMMUNE FUNCTION

有令人信服的证据表明，在这两种情况下都存在内源性大麻素 大脑和免疫系统。两个G蛋白偶联的大麻素 受体已经被克隆。一种是在整个大脑中发现的高 浓度，以及在几个外周组织中，而 其他则仅限于外围设备。与世隔绝和 鉴定内源性大麻素，如阿南达胺，导致 加强努力，以了解 内源性大麻素。对这些内源性配体的操纵应该 揭示它们的功能作用，特别是通过大麻素介导的作用 受体，并有助于更好地了解大麻的病因学 滥用，确定大麻类药物的治疗用途，以及 确立对免疫的有害或保护作用 系统。对免疫系统的研究很重要，因为它们可能会 为了阐明内源性大麻素调节的机制 免疫功能。这种调制在免疫系统中可能有影响 受危害的个人，特别是艾滋病患者。最近的事态发展 一种有效的大麻素拮抗剂SR141716A的作用是一种令人兴奋的新 为实现这些目标进行探索。这项建议的目的是 建立一个由六个研究项目组成的多学科项目 和行政核心，以定义内源性的功能作用 大麻素。每一位私家侦探都是经验丰富的研究人员，他们会做出 独一无二的贡献。Mechoulam教授建议隔离和识别 来自组织部分的其他内源性大麻素，表现出 大麻素活性。拉兹丹博士将在 他将为该组织的其他成员提供新颖和创新的探索 研究团队。他的目标包括准备稳定和高度 内源性物质的有效类似物和SR141716A的类似物。Dr。 马丁的研究小组将对其进行药理学评估 内源性激动剂的内源性配体及其类似物 对抗者。该小组还将同时使用容忍度开发和 拮抗剂探讨受体的可塑性和基因表达。 Aceto博士将确定慢性前列腺炎的药理学后果 Delta9-THC和双胺对大鼠的暴露及其依赖性评价 责任。卡布拉尔和卡明斯基博士建议建立 内源性配体对免疫系统的影响及阐明其天然作用 大麻素对免疫功能的影响。卡明斯基博士有证据表明 内源性配体对免疫细胞有不同的作用。卡布拉尔博士 假设内源性配体减弱巨噬细胞的功能 可以为艾滋病患者的大脑提供神经保护。这个 通过一个项目协调这个非常成功的研究团队 项目机制应该是富有成效的。

There is convincing evidence that endogenous cannabinoids exist in both the brain and the immune system. Two G-protein coupled cannabinoid receptors have been cloned. One is found throughout the brain in high concentrations, as well as in several peripheral tissues, whereas the other is localized exclusively in the periphery. The isolation and identification of endogenous cannabinoids, such as anandamide, led to intensified efforts to understand the functional significance of endogenous cannabinoids. Manipulation of these endogenous ligands should reveal their functional role, especially as mediated through cannabinoid receptors, and lead to a better understanding of the etiology of cannabis abuse, identification of therapeutic uses of cannabinoids, and establishment of either deleterious or protective effects on the immune system. Studies on the immune system are important since they may allow for articulation of a mechanism by which endogenous cannabinoids modulate immune function. Such modulation may be of consequence among immune compromised individuals, especially AIDS patients. The recent development of SR141716A, a potent cannabinoid antagonist, serves as an exciting new probe for fulfilling these objectives. The purpose of this proposal is to establish a multidisciplinary program, consisting of six research projects and an administrative core, to define the functional role of endogenous cannabinoids. Each P.I. is an experienced researcher who will make a unique contribution. Professor Mechoulam proposes to isolate and identify other endogenous cannabinoids from tissue fractions which exhibit cannabinoid activity. Dr. Razdan will carry out a synthetic program in which he will provide novel and innovative probes to the other members of the research team. His objectives include preparation of stable and highly potent analogs of the endogenous substances and analogs of SR141716A. Dr. Martin's research group will conduct pharmacological evaluation of endogenous ligands and analogs of endogenous agonists and of the antagonist. This group also will use both tolerance development and the antagonist to explore the plasticity of the receptor and gene expression. Dr. Aceto will determine the pharmacological consequences of chronic exposure of delta9-THC and anandamide to rats and assess their dependence liability. Drs. Cabral and Kaminski propose to establish the effects of endogenous ligands on the immune system and to elucidate a natural role of cannabinoids in immune function. Dr. Kaminski has evidence that two endogenous ligands exert different effects on immune cells. Dr. Cabral hypothesizes that endogenous ligands attenuate macrophage function which could provide neuroprotection in the brain of AIDS patients. The coordination of this highly successful research team through a program project mechanism should be highly productive and fruitful.