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.

此应用程序中概述的工作在于两个我们社会的紧迫问题，药物滥用和艾滋病大流行。尽管新艾滋病案件的发生率一直在下降传统的高风险群体静脉吸毒者中的问题是恶化。有证据表明鸦片具有潜力为了抑制免疫系统，不幸的是，这一事实可能会创造一个 i.v.的情况吸毒者正在将自己置于生物学，类型的“双重危险”。文学包含一个表明阿片类药物能够影响的报告数量免疫系统的功能，吗啡的机制成瘾会改变免疫反应尚不清楚。但是，似乎诸如吗啡之类的鸦片可能会对免疫产生直接影响系统或间接的系统。间接机制可能涉及改变水平的神经内分泌激素。有证据这表明阿片类药物能够通过直接和间接机制。我们计划的假设测试是； “吗啡后观察到的深刻免疫抑制给小鼠的施用不是单一机制。吗啡对免疫细胞的直接影响是由其他与吗啡在大脑中的作用有关的免疫抑制事件。这些间接的吗啡的间接免疫抑制作用涉及下丘脑 - 垂体 - 肾上腺（HPA）轴以及同情神经系统（SNS）。“评估该假设的有效性，提出了以下特定目的：（1）定义在植入的小鼠中观察到的胸腺萎缩和体液抑制带有吗啡颗粒。（2）阻止计算的机制在用吗啡治疗的小鼠中观察到的体内胸腺萎缩。（3）确定吗啡导致体内抑制的机制脾脏的体液免疫反应对注射SRBC的反应。到完成这些目标是体外和体内研究的结合计划。实验旨在更好地定义免疫力在吗啡治疗的小鼠中出现的缺陷，并确定哪个免疫系统的细胞最易感。吗啡主要相对于继发免疫反应的敏感性将是检查。流式细胞仪将用于确定吗啡后从脾和胸腺中耗尽的细胞治疗。识别凋亡作为的研究是吗啡诱导胸腺萎缩，并进行实验评估HPA轴和SN在启动它中的作用。实验将执行以确定吗啡的相对贡献直接与抑制抗体的间接影响脾脏的反应。分离宪法研究将确定抗体响应中的细胞或细胞在起作用亚正常。提议的实验的完成应有助于对直接和神经免疫机制的理解吗啡能够抑制免疫力。