Behavioral Factors in Heroin's Effect on Nitric Oxide

描述(申请人提供)：海洛因依赖者的传染病发病率很高。尽管海洛因使用带来了重大的健康问题，但很少有研究研究海洛因对免疫状态的影响。大量的最新数据表明，一氧化氮在决定接触某些病原体的结局中起着关键作用。本实验室首次提供了海洛因给药引起诱导型一氧化氮表达改变的证据。具体目的I在革兰氏阳性、革兰氏阴性感染和多菌感染模型中检验海洛因诱导一氧化氮产生改变的假设。这项拟议的研究调查了海洛因对革兰氏阴性和革兰氏阳性细菌感染模型中一氧化氮产生的影响。这些研究调查了注射免疫原性细菌成分：脂多糖(革兰氏阴性)、脂磷壁酸(革兰氏阳性)以及与肽聚糖联合注射后海洛因对一氧化氮产生的剂量依赖性影响。随后的研究将通过单一感染典型的革兰氏阴性类杆菌和革兰氏阳性B组链球菌的活细菌挑战，以及盲肠结扎和穿孔模型(CLP)，来研究海洛因对一氧化氮表达的影响。特定目的II在革兰氏阳性和革兰氏阴性感染以及多菌感染模型中测试海洛因诱导的一氧化氮表达变化的条件性作用。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会导致一氧化氮表达的变化。建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，包括对条件性反应的获得和消亡的评估。在感染模型中，特定目标III验证了中枢多巴胺能系统参与调节海洛因诱导的一氧化氮表达变化的假设。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性和非条件性影响。这项拟议的研究考察了中枢多巴胺在无条件和条件性海洛因诱导的一氧化氮表达变化中的作用。拟议的实验将确定7-OH-DPAT和D1选择性拮抗剂SCH23390在海洛因诱导的感染成分和活体模型中一氧化氮变化的影响。总的来说，在细菌注射模型中海洛因诱导的诱导性一氧化氮调节的特征提供了对阿片类药物如何影响免疫系统和健康的更好的理解。

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.