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) 该提案是针对探索性/开发性拨款申请(R21)， 专门针对RFA#PAR-01-047，袖口边缘基础研究奖 (Cebra)计划。近年来，已分离出胍丁胺(脱羧精氨酸)。 从哺乳动物的脑和脊髓中分离出来，发现能拮抗NMDA受体和 抑制一氧化氮合酶(NOS)。因为谷氨酸被认为可以驱动 通过一系列激活NMDA受体和NOS的突触可塑性， 胍丁胺可能参与控制突触可塑性及相关 行为现象(例如，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。外源性给药 胍丁胺在脑缺血模型中具有神经保护作用(Gilad，1996)和 脊髓损伤(Yu et.等人，2000年)，并防止阿片类药物的发展 止痛耐受性(Kolesnikov，1996；费尔班克斯，1997)，都被认为是 需要可塑性的过程。除了这些已发表的报告外， 这里提供的初步数据表明，外源性胍丁胺可以预防 芬太尼自主给药。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的镇痛作用 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类药物耐受性的关系 自治。首先，胍丁胺浓度将系统地 在被认为与阿片类药物有关的大脑和脊髓区域进行了测量 成瘾和止痛药耐受性。这些测量值将在以下范围内进行比较 已知的多个品系的小鼠对诱导具有不同的敏感性 阿片类止痛药耐受性和自我给药。如果，作为外生性 胍丁胺的研究结果预测，内源性胍丁胺可以防止诱导 阿片类止痛剂耐受性和自身给药，然后小鼠品系与 浓度相对较低的中枢神经系统胍丁胺将更多 对诱导的敏感性高于高浓度的中枢胍丁胺，以及 负相关。项目的第二个组成部分将决定是否 操纵中枢胍丁胺水平改变镇痛耐受性和 自我管理也通过一种反向关系进行。这些研究的结果 拟议的第一阶段CEBRA R21研究将确定是否存在 内源性胍丁胺与谷氨酸能神经递质的调节关系 阿片类药物耐受和自我给药的机制。这样的发现 将为深入机械地澄清以下问题提供理由 内源性胍丁胺在阿片类镇痛耐受中的作用 自我管理，这一战略将构成下一个阶段11 Cebra R01应用程序。阐明内源性胍丁胺在心肌梗死中的作用 调节阿片类药物耐受和自我给药的发展可能 导致开发一类新的药物或替代方法来 治疗成瘾，或确定新的治疗靶点。