Agmatinergic Control of Opioid Tolerance and Drug Abuse

阿片类药物耐受性和药物滥用的阿片能控制

• 批准号: 6508261
• 负责人: Carolyn A Fairbanks
• 金额: $ 17.35万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-15 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6508261
• 关键词: analgesics; antisense nucleic acid; arginine; behavioral /social science research tag; brain mapping; chemical structure function; drug abuse; drug addiction; drug tolerance; endogenous opioid; genetic strain; guanidines; high performance liquid chromatography; laboratory mouse; laboratory rat; microdialysis; neuroregulation; nucleus accumbens; self medication; spinal cord; tegmentum

DESCRIPTION: (provided by applicant) This proposal is for an Exploratory/Developmental Grant Application (R21), specifically addressing RFA # PAR-01-047, the Cuffing Edge Basic Research Award (CEBRA) program. Recently, agmatine (decarboxylated arginine) has been isolated from mammalian brain & spinal cord and found to antagonize NMDA receptors and inhibit nitric oxide synthase (NOS). Because glutamate is thought to drive synaptic plasticity by activating both NMDA receptors and NOS in series, agmatine may participate in control of synaptic plasticity and related behavioral phenomena (e.g. learning, memory, chronic pain, opioid tolerance and self-administration) as a neuromodulator of glutamate. Exogenously administered agmatine is neuroprotective in models of cerebral ischemia (Gilad, 1996) and spinal cord injury (Yu et. al., 2000) and prevents development of opioid analgesic tolerance (Kolesnikov 1996; Fairbanks, 1997), all considered to be processes requiring plasticity. In addition to these published reports, preliminary data presented here demonstrates that exogenous agmatine prevents fentanyl self-administration. The primary goal of the proposed study is to determine whether endogenous agmatine modulates opioid-induced analgesic tolerance and self-administration. That objective will be addressed by determining the relationship of agmatine levels to opioid tolerance and self-administration. First, agmatine concentration will be systematically measured in brain and spinal cord regions thought to be involved in opioid addiction and analgesic tolerance. These measurements will be compared across multiple strains of mouse known to have differential sensitivities to induction of opioid analgesic tolerance and self-administration. If, as exogenous agmatine findings predict, endogenous agmatine protects against induction of opioid analgesic tolerance and self -administration, then mouse strains with relatively low concentrations of central nervous system agmatine will be more sensitive to induction than those with high concentrations of CNS agmatine, an inverse correlation. The second component of the project will determine whether manipulating levels of CNS agmatine changes analgesic tolerance and self-administration also through an inverse relationship. The results of these proposed Phase I CEBRA R21 studies will determine whether or not there exists a modulatory relationship between endogenous agmatine and the glutamatergic mechanisms underlying opioid tolerance and self-administration. Such a finding would provide a rationale for pursuing in depth mechanistic clarification of the role of endogenous agmatine in opioid analgesic tolerance and self-administration, a strategy that would comprise the subsequent PHASE 11 CEBRA R01 application. Elucidation of a role for endogenous agmatine in modulation of the development of opioid tolerance and self-administration may lead to the development of a novel class of drugs or alternative methods to treat addiction, or to the identification of new therapeutic targets.

描述：（申请人提供） 本提案适用于探索/发展补助金申请（R21）， 特别针对RFA # PAR-01-047，袖口边缘基础研究奖 （CEBRA）计划。最近，胍丁胺（脱羧精氨酸）已被分离 从哺乳动物的大脑和脊髓，并发现拮抗NMDA受体， 抑制一氧化氮合酶（NOS）。因为谷氨酸被认为是 突触可塑性通过激活NMDA受体和NOS串联， 胍丁胺可能参与控制突触可塑性和相关的 行为现象（如学习、记忆、慢性疼痛、阿片类药物耐受和 自我给药）作为谷氨酸的神经调节剂。外源施用的 胍丁胺在脑缺血模型中具有神经保护作用（Gilad，1996）， 脊髓损伤（Yu et.例如，2000）并防止阿片类药物的发展 镇痛耐受性（Kolesnikov 1996;费尔班克斯，1997），均被认为是 需要可塑性的过程。除了这些公布的报告外， 这里提供的初步数据表明，外源性胍丁胺可预防 芬太尼自我给药。拟议研究的主要目标是 确定内源性胍丁胺是否调节阿片类药物诱导的镇痛 宽容和自我管理。这一目标将通过以下方式实现： 确定胍丁胺水平与阿片耐受性的关系， 自我管理。首先，将系统地测定胍丁胺浓度 在被认为与阿片类药物有关的大脑和脊髓区域测量 成瘾和镇痛耐受性。这些测量结果将在 已知对诱导具有不同敏感性的多种小鼠品系 阿片类镇痛药耐受性和自我给药的能力。如果作为外源性的 胍丁胺研究结果预测，内源性胍丁胺可防止诱导 阿片类镇痛剂耐受性和自我给药，然后小鼠品系与 中枢神经系统胍丁胺浓度相对较低， 对诱导的敏感性高于具有高浓度CNS胍丁胺的那些， 反相关该项目的第二部分将确定是否 控制中枢神经系统胍丁胺的水平会改变镇痛耐受性， 自我管理也是通过一种相反的关系。的结果予以 拟议的I期CEBRA R21研究将确定是否存在 内源性胍基丁胺与谷氨酸能之间的调节关系 阿片类药物耐受性和自我给药的潜在机制。这样的发现 将提供一个深入的机制澄清， 内源性胍丁胺在阿片类镇痛耐受中作用 自我管理，这一战略将包括随后的第11阶段 CEBRA R 01应用程序。阐明内源性胍丁胺在 调节阿片样物质耐受性和自我给药的发展可以 导致开发一类新的药物或替代方法， 治疗成瘾，或识别新的治疗靶点。