NEUROIMMUNE MECHANISMS OF MORPHINE IMMUNOSUPPRESSION

吗啡免疫抑制的神经免疫机制

基本信息

批准号：
2119723
负责人：
JOHN A ROSECRANS
金额：
$ 14.66万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-08-01 至 1995-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2119723
关键词：
antibody formation apoptosis atrophy cell population study cell sorting humoral immunity hypothalamic pituitary axis immunosuppression laboratory mouse morphine neuroendocrine system neuroimmunomodulation pituitary adrenal axis spleen thymus

项目摘要

The work outlined in this application lies at the intersection of two of our society's pressing problems, drug abuse and the AIDS pandemic. While the incidence of new AIDS cases has been declining among some of the traditional high risk groups the problem among intravenous drug users is worsening. There is evidence to indicate that opiates have the potential to suppress the immune system and, unfortunately, this fact may create a situation in which i.v. drug abusers are placing themselves in a biological, type of "double jeopardy." While the literature contains a number of reports which suggest that opiates are able to affect the functioning of the immune system, the mechanism by which morphine addiction alters the immune response is not clear. However, it seems that an opiate such as morphine may have a direct effect on the immune system or, alternatively, an indirect one. The indirect mechanism may involve altered levels of neuroendocrine hormones. There is evidence which suggests that opiates are able to affect the immune system through both direct and indirect mechanisms. The hypothesis which we plan to test is; "The profound immunosuppression observed following morphine administration to mice is not attributable to a single mechanism. Morphine's direct effects on immunologic cells are compounded by other immunosuppressive events which relate to morphine's actions in the brain. These indirectly immunosuppressive actions of morphine involve the hypothalamic-pituitary-adrenal (HPA) axis as well as the sympathetic nervous system (SNS)." To evaluate the validity of this hypothesis, the following specific aims are proposed: (1) Define the parameters of the thymic atrophy and humoral immune suppression observed in mice implanted with a morphine pellet. (2) Deter-mine the mechanisms which account for the marked in vivo thymic atrophy observed in mice treated with morphine. (3) Determine the mechanisms by which morphine causes in vivo suppression of the splenic humoral immune response to an injection of SRBC. To accomplish these aims a combination of in vitro and in vivo studies are planned. Experiments have been designed to better define the immune deficits which occur in morphine treated mice and to determine which cells of the immune system are most susceptible. The morphine susceptibility of primary relative to secondary immune responses will be examined. Flow cytometry will be used to identify the subpopulations of cells which are depleted from the spleen and thymus following morphine treatment. Studies to identify apoptosis as the mechanism by which morphine induces thymic atrophy are planned, as well experiments to assess the role of the HPA axis and SNS in initiating it. Experiments will be performed to determine the relative contribution of morphine's direct vs. it's indirect effects in the suppression of the antibody response in the spleen. Separation-reconstitution studies will identify the cell, or cells, in the antibody response which are functioning subnormally. Completion of the proposed experiments should contribute to an understanding of the direct and neuroimmune mechanisms through which morphine is able to suppress immunity.

本申请中概述的工作位于以下两者的交叉点我们社会面临的紧迫问题：药物滥用和艾滋病流行。尽管一些国家的艾滋病新病例发病率一直在下降传统高危人群静脉吸毒者的问题是恶化。有证据表明阿片类药物具有潜力抑制免疫系统，不幸的是，这一事实可能会产生 i.v. 的情况吸毒者将自己置于一个生物学上的“双重危险”类型。虽然文献中包含许多报告表明阿片类药物能够影响免疫系统的功能，吗啡的机制成瘾会改变免疫反应尚不清楚。然而，似乎吗啡等阿片类药物可能对免疫有直接影响系统，或者间接系统。间接机制可能涉及神经内分泌激素水平的改变。有证据这表明阿片类药物能够通过以下方式影响免疫系统：直接机制和间接机制。我们计划的假设测试是； “吗啡后观察到的严重免疫抑制对小鼠的给药不归因于单一机制。吗啡对免疫细胞的直接影响与其他因素相结合与吗啡在大脑中的作用有关的免疫抑制事件。吗啡的这些间接免疫抑制作用涉及下丘脑-垂体-肾上腺 (HPA) 轴以及交感神经神经系统（SNS）。”为了评估这一假设的有效性，提出以下具体目标： (1) 定义参数在植入小鼠中观察到胸腺萎缩和体液免疫抑制与吗啡丸。 (2) 确定解释机制在用吗啡治疗的小鼠中观察到明显的体内胸腺萎缩。 (3)确定吗啡引起体内抑制的机制注射 SRBC 后的脾体液免疫反应。到结合体外和体内研究来实现这些目标计划。实验旨在更好地定义免疫吗啡治疗小鼠中出现的缺陷并确定哪些缺陷免疫系统的细胞最容易受到影响。吗啡初级免疫反应相对于次级免疫反应的敏感性将是检查了。流式细胞术将用于鉴定亚群吗啡后脾脏和胸腺中的细胞被耗尽治疗。研究确定细胞凋亡的机制吗啡诱导胸腺萎缩的实验已计划进行评估 HPA 轴和 SNS 在启动过程中的作用。实验将进行以确定吗啡的相对贡献抑制抗体的直接作用与间接作用反应在脾。分离-重构研究将确定抗体反应中发挥作用的一个或多个细胞低于正常水平。完成拟议的实验应有助于了解直接和神经免疫机制吗啡能够抑制免疫力。