Behavioral Factors in Heroin's Effect on Nitric Oxide

描述（由申请人提供）：海洛因依赖者感染性疾病的发病率很高。尽管海洛因使用的主要健康问题，很少有研究探讨海洛因对免疫状态的影响。最近大量的数据表明，一氧化氮在确定暴露于某些病原体的结果中起着关键作用。我们的实验室提供了第一个证据表明，海洛因管理产生的诱导型一氧化氮的表达改变。具体目的我测试的假设，海洛因诱导革兰氏阳性菌，革兰氏阴性菌感染，和多微生物感染模型中的一氧化氮产生的改变。拟议的研究调查海洛因对一氧化氮生产的革兰氏阴性和革兰氏阳性细菌感染模型的影响。这些研究调查了注射免疫原性细菌成分后海洛因对一氧化氮产生的剂量依赖性影响：脂多糖（革兰氏阴性）、单独的脂磷壁酸（革兰氏阳性）和与肽聚糖的组合。随后的研究将检查海洛因对一氧化氮表达的影响，使用活的细菌挑战，具有革兰氏阴性拟杆菌和革兰氏阳性B族链球菌的代表性脓毒症能力菌株的单一感染，以及盲肠结扎穿孔模型（CLP），一种多微生物感染挑战。具体目标II测试海洛因诱导的一氧化氮表达的改变在革兰氏阳性菌和革兰氏阴性菌感染，和多微生物感染模型的条件作用。越来越多的证据表明，巴甫洛夫条件反射过程可以调节免疫反应。我们的实验室提供了第一个数据，表明环境刺激与海洛因配对诱导一氧化氮表达的改变。拟议的研究将这一重要发现扩展到革兰氏阴性和革兰氏阳性细菌感染的模型以及混合感染CLP模型，包括条件反应的获得和消退的评估。具体目标III测试的假设，中央多巴胺能系统参与海洛因诱导的一氧化氮表达的变化在感染模型的调节。我们的实验室提供了新的数据，表明多巴胺参与了阿片类药物对免疫反应的条件和非条件作用。拟议的调查研究的作用，中央多巴胺在无条件和条件海洛因诱导的一氧化氮表达的变化。拟议的实验将确定7-OH-DPAT和D1-选择性拮抗剂，SCH 23390，对海洛因诱导的一氧化氮的变化在组件和活的感染模型的效果。总的来说，在细菌注射模型中海洛因诱导的诱导型一氧化氮调节的表征提供了对阿片类药物如何影响免疫系统和健康的更好理解。

DESCRIPTION (provided by applicant): 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 nitric oxide plays a pivotal role in determining the outcome of exposure to certain pathogens. Our laboratory has provided the first evidence that heroin administration produces alterations of the expression of inducible nitric oxide. Specific Aim I tests the hypothesis that heroin induces alterations of nitric oxide production in models of Gram-positive, Gram-negative infection, and polymicrobial infection. The proposed studies investigate the effects of heroin on nitric oxide production in models of both Gram-negative and Gram-positive bacterial infection. These studies investigate the dose-dependent effects of heroin on the production of nitric oxide following injection of immunogenic bacterial components: lipopolysaccharide (Gram-negative), lipoteichoic acid alone (Gram-positive) and in combination with peptidoglycan. Subsequent studies will examine the effects of heroin on nitric oxide expression using live bacterial challenges with monoinfections of representative sepsis-capable strains of Gram-negative bacteroides and Gram-positive Group B streptococci, and the ceca-ligation and puncture model (CLP), a polymicrobial infection challenge. Specific Aim II tests the conditioned effects of heroin-induced alterations of nitric oxide expression in models of Gram-positive and Gram-negative infection, and polymicrobial infection. There is growing evidence that Pavlovian conditioning processes can modulate immune responses. Our laboratory has provided the first data showing that environmental stimuli paired with heroin-induce alterations of nitric oxide expression. The proposed studies extend this important discovery to models of both Gram-negative and Gram-positive bacterial infection, and the mixed infection CLP model, including assessments of acquisition and extinction of conditioned responses. Specific Aim III tests the hypothesis that the central dopaminergic systems are involved in the regulation of heroin-induced alterations of nitric oxide expression in models of infection. Our laboratory has provided new data showing that dopamine is involved in the conditioned and unconditioned effects of opioids on immune responses. The proposed investigations examine the role of central dopamine in unconditioned and conditioned heroin-induced alterations of nitric oxide expression. The proposed experiments will determine the effect of 7-OH-DPAT and the D1-selective antagonist, SCH23390, on heroin-induced alterations of nitric oxide in both the component and live models of infection. Collectively, the characterization of heroin-induced modulation of inducible nitric oxide in bacterial injections models provides a greater understanding of how opioids impact the immune system and health.