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.

传染病的发生率很高 海洛因依赖人。尽管存在围绕的重大健康问题 海洛因使用，很少有研究检查海洛因对免疫状态的影响。一个 最近的数据表明，一氧化氮的诱导作用 在对传染病的免疫反应中的关键作用。来自我们的新数据 实验室提供了海洛因管理生产的第一个证据 诱导型一氧化氮合酶（iNOS）的改变，酶负责 用于生产一氧化氮。具体目的我广泛测试 海洛因在体内表达中引起广泛改变的假设 nos。这个特定目的完全评估了海洛因对 Lipopolyscaride（LPS）诱导的iNOS表达。实验建立 海洛因的剂量效应关系以及那些的对抗 纳曲酮的影响。为了测量体内的NOS生产，我们两者都采用 RT-PCR和Western印迹，以测量iNOS mRNA表达的改变和 脾脏，肺和肝组织中的蛋白质。我们还测量了亚硝酸盐/硝酸盐 等离子体。特定的目标II检验了海洛因引起的改变的假设 NOS的生产由与药物配对的环境刺激条件 行政。可以诱导免疫改变的证明 与海洛因给药相关的刺激很重要，因为它表明 海洛因使用的有害健康后果的条件是 环境刺激，而不仅仅是该药物的药理特性。 拟议的研究决定了海洛因对一氧化氮的影响是否 可以通过环境刺激与海洛因搭配产生生产 行政。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 调节程序涉及的辅助因素。灭绝测试 潜在的抑制作用将确定效果遵循 帕夫洛夫调节。特定的AIMIII检验了药物的假设 自我管理是控制海洛因的重要行为变量 对一氧化氮生产的影响。自我管理范式 提供了一种与海洛因评估的临床相关方法 对一氧化氮生产的影响。该研究比较了海洛因的影响 自助给被动药物管理员。调查 自我管理的海洛因对一氧化氮生产的影响是由 证据表明，对药物管理局的控制极大地影响了 生理效应。海洛因是差异化的演示 有效地改变一氧化氮的产生，具体取决于药物是否 是自我管理或被动注入的 海洛因使用的健康后果。总体上的特征 海洛因诱导的诱导一氧化氮合酶的调节 对阿片类药物如何影响免疫系统和 健康。