BEHAVIORAL FACTORS IN HEROIN'S EFFECT ON NITRIC OXIDE

海洛因对一氧化氮影响的行为因素

• 批准号: 6379054
• 负责人: DONALD T LYSLE
• 金额: $ 18.06万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6379054
• 关键词: blood chemistry; conditioning; enzyme activity; enzyme induction /repression; heroin; immunomodulators; laboratory rat; lipopolysaccharides; naltrexone; neuropharmacology; nitrates; nitric oxide; nitric oxide synthase; nitrites; polymerase chain reaction; psychopharmacology; self medication; western blottings

There is a high incidence of infectious disease in heroin-dependent individuals. In spite of the major health issues surrounding heroin use, few studies have examined the impact of heroin on immune status. A wealth of recent data has revealed that the induction of nitric oxide plays a critical role in the immune response to infectious diseases. New data from our laboratory has provided the first evidence that heroin administration produces alterations of inducible nitric oxide synthase (iNOS), the enzyme responsible for the production of nitric oxide. Specific Aim I extensively tests the hypothesis that heroin induces widespread alterations in the in vivo expression of NOS. This specific aim fully evaluates the effect of heroin on lipopolysaccaride (LPS)-induced iNOS expression. The experiments establish dose-effect relationships for heroin, as well as the antagonism of those effects with naltrexone. To measure NOS production in vivo, we employ both RT-PCR and western blotting to measure alterations of iNOS mRNA expression and protein in spleen, lung, and liver tissue. We also measure nitrite/nitrate in plasma. Specific Aim II tests the hypothesis that heroin-induced alteration of NOS production is conditioned to environmental stimuli paired with drug administration. The demonstration that immune alterations can be induced by the stimuli associated with heroin administration is important for it indicates that the detrimental health consequences of heroin use are conditioned to environmental stimuli and not solely the pharmacological property of the drug. The proposed studies determine whether heroin's effect on nitric oxide production can be elicited by environmental stimuli paired with heroin administration. Control procedures are used to assure that these conditioned alterations are due to conditioning processes per se, and not the result of ancillary factors involved in the conditioning procedure. Tests of extinction and latent inhibition will establish that the effects follow the principles of Pavlovian conditioning. Specific AimIII tests the hypothesis that drug self-administration is an important behavioral variable controlling heroin's effect on the production of nitric oxide. The self-administration paradigm provides a clinically relevant methodology for the assessment of heroin's effects on nitric oxide production. The study compares the effects of heroin self-administration to those of passive drug administration. Investigation of the effects of self-administered heroin on nitric oxide production is driven by evidence showing that control over drug administration greatly influence it's physiological effects. The demonstration that heroin is differentially efficacious in altering nitric oxide production depending upon whether the drug is self-administered or passively infused has important implications for the health consequences of heroin use. Collectively, the characterization of heroin-induced modulation of inducible nitric oxide synthase production provides a greater understanding of how opioids impact the immune system and health.

年的传染病发病率很高。 海洛因依赖者尽管存在重大的健康问题， 关于海洛因的使用，很少有研究探讨海洛因对免疫状况的影响。一 最近大量的数据显示，一氧化氮的诱导在 在对传染病的免疫反应中起关键作用。来自我们的新数据 实验室提供了海洛因管理产生的第一个证据， 诱导型一氧化氮合酶（iNOS）的改变， 一氧化氮的合成具体目标I广泛测试 海洛因诱导体内表达广泛改变的假说 的NOS。这一具体目标充分评估了海洛因对 脂多糖（LPS）诱导的iNOS表达。实验证明， 海洛因的剂量效应关系，以及这些拮抗作用 与naldipone的作用为了测量体内NOS的产生，我们采用了 RT-PCR和Western blotting检测iNOS mRNA表达的变化， 脾、肺和肝组织中的蛋白质。我们还测量亚硝酸盐/硝酸盐， 等离子体具体目标II测试海洛因诱导的改变的假设， 一氧化氮合酶的产生受环境刺激和药物的影响 局证明免疫改变可以由 与海洛因给药相关的刺激很重要，因为它表明 使用海洛因的有害健康后果是有条件的， 环境刺激，而不仅仅是药物的药理学性质。 这项研究旨在确定海洛因对一氧化氮的影响是否 环境刺激与海洛因结合可以诱发产生 局控制程序用于确保这些条件 改变是由于调节过程本身，而不是由于 调节过程中涉及的辅助因素。灭绝试验 和潜在的抑制作用将确定这些效应遵循以下原则： 巴甫洛夫条件反射。特异性AimIII检验了药物 自我给药是控制海洛因依赖的重要行为变量 影响一氧化氮的产生。自我管理范式 提供了一个临床相关的方法来评估海洛因的 对一氧化氮产生的影响。这项研究比较了海洛因 自我给药与被动给药相比。调查 自我注射海洛因对一氧化氮产生的影响是由 有证据表明，对药品管理的控制对其影响很大 生理效应。证明海洛因与 有效改变一氧化氮的产生取决于药物是否 是自我管理或被动输注有重要的影响， 海洛因使用的健康后果。总的来说， 海洛因对诱导型一氧化氮合酶产生调节作用 更好地了解阿片类药物如何影响免疫系统， 健康