Modulation of G protein coupled receptor function

G 蛋白偶联受体功能的调节

• 批准号: 6575398
• 负责人: Steven R Childers
• 金额: $ 20.62万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-15 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6575398
• 关键词: G protein; NMDA receptors; adenosine; adenylate cyclase; analgesia; analgesics; autoradiography; chronic pain; clonidine; drug tolerance; guanine nucleotide binding protein; inhibitor /antagonist; laboratory rat; morphine; nervous system disorder chemotherapy; neuropharmacology; nonhuman therapy evaluation; opioid receptor; protein kinase C; protein structure function; purinergic receptor; receptor binding; receptor coupling; spinal cord; stimulant /agonist

Opioid agonists like morphine, codeine and meperidine remain the most commonly used and effective treatment for chronic pain conditions. Despite the fact that chronic opioid treatment can produce high levels of tolerance and physical dependence. Mechanisms of tolerance and dependence for in brain are not well understood, but it is clear that chronic opioid treatment produces significant receptor desensitization in specific brain regions. Moreover, pain itself, as well as concurrent treatment with drugs like adenosine and alpha2- adrenergic agonists, alter the sensitivity of patients to opioid treatment. Opioid receptors (including mu, delta and kappa types), as well as adenosine A1 and alpha2-adrenergic receptors, are G-protein-coupled receptors, and their ability to activate signal transduction systems can be determined by the ability of agonists to stimulate [35S]GTPgammaS binding in both membranes and section autoradiography. This project will examine regulation of several receptor/G-protein interactions in rat spinal cord, using models of drug treatment, self-administration and chronic pain developed by other Center components. First, after determining the acute efficacies of opioid and adenosine A1 agonists in activating G-proteins in spinal cord, the ability of chronic drug exposure to produce receptor desensitization will be examined in both spinal cord membranes and by autoradiography. These treatments will include chronic intrathecal opioid administration to desensitize opioid receptor-activated G-proteins, and chronic intrathecal administration of adenosine and clonidine to desensitize agonist-stimulated incorporation of [32P]AAGTP into specific G-protein subunits. Second, various receptor-activated G-protein activities will be determined in both brains ans spinal cords from spinal nerve ligated rats to determine whether chronic pain and hypersensitivity affect receptor/G-protein coupling. These studies will also determine how chronic pain states modulate basal levels and activities of G-proteins in spinal cord. Third, the ability of NMDA antagonists and protein kinase C inhibitors to modulate receptor desensitization will be tested after chronic intrathecal administration of drugs. Information from this project will help design studies in the Clinical Core to test the use of opioid agonists of differing efficacies in treating chronic pain. Moreover, these studies will provide information to minimize tolerance in long-term drug treatment of chronic pain.

吗啡、可待因和哌替啶等阿片类激动剂仍然是治疗慢性疼痛最常用和最有效的方法。尽管事实上，长期阿片类药物治疗会产生高水平的耐受性和身体依赖性。 大脑中的耐受和依赖性机制尚不清楚，但很明显，长期阿片类药物治疗会在特定大脑区域产生显着的受体脱敏。 此外，疼痛本身以及腺苷和α2-肾上腺素能激动剂等药物的同时治疗会改变患者对阿片类药物治疗的敏感性。阿片受体（包括mu、delta和kappa型）以及腺苷A1和α2肾上腺素能受体都是G蛋白偶联受体，它们激活信号转导系统的能力可以通过激动剂刺激的能力来决定。 35S]GTPgammaS 在膜和切片放射自显影中结合。 该项目将利用中心其他部门开发的药物治疗、自我给药和慢性疼痛模型，研究大鼠脊髓中几种受体/G 蛋白相互作用的调节。 首先，在确定阿片类药物和腺苷 A1 激动剂激活脊髓 G 蛋白的急性功效后，将在脊髓膜和放射自显影中检查长期药物暴露产生受体脱敏的能力。 这些治疗将包括长期鞘内施用阿片类药物以使阿片受体激活的 G 蛋白脱敏，以及长期鞘内施用腺苷和可乐定以使激动剂刺激的 [32P]AAGTP 掺入特定 G 蛋白亚基脱敏。 其次，将测定脊髓神经结扎大鼠的大脑和脊髓中的各种受体激活的 G 蛋白活性，以确定慢性疼痛和超敏反应是否影响受体/G 蛋白偶联。这些研究还将确定慢性疼痛状态如何调节脊髓中 G 蛋白的基础水平和活性。 第三，在长期鞘内给药后，将测试NMDA拮抗剂和蛋白激酶C抑制剂调节受体脱敏的能力。 该项目的信息将有助于设计临床核心研究，以测试使用不同功效的阿片类激动剂治疗慢性疼痛。 此外，这些研究将提供信息，以最大限度地减少慢性疼痛长期药物治疗的耐受性。