NEUROSCIENCE - SUBPROJECT 1: MODULATION OF MORPHINE TOLERANCE BY ANTI-OPIATE PEP

神经科学 - 子项目 1：通过抗阿片类药物 PEP 调节吗啡耐受性

• 批准号: 7715253
• 负责人: CARL B GOODMAN
• 金额: $ 11.2万
• 依托单位: FLORIDA AGRICULTURAL AND MECHANICAL UNIV
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7715253
• 关键词: Agonist; Attenuated; Brain region; Cerebral cortex; Cerebrospinal Fluid; Cerebrum; Chronic; Complex; Computer Retrieval of Information on Scientific Projects Database; Corpus striatum structure; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dependence; Development; Funding; GTP-Binding Proteins; Glutamine; Grant; Infusion procedures; Institution; Intraventricular Infusion; Measures; Modeling; Morphine; Morphine Sulfate; Neurosciences; Opiates; Opioid Receptor; Pump; Rattus; Receptor Signaling; Research; Research Personnel; Resources; Signal Transduction Pathway; Source; Spinal Cord; System; Testing; Thalamic structure; United States National Institutes of Health; arginylphenylalaninamide; day; indexing; leucyl-phenylalanine; mu opioid receptors; neuropeptide FF; neuropeptide FF receptor; phenylalanylleucine; receptor; receptor density; research study

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The underlying mechanism(s) of opiate tolerance remains to be elucidated. Neuropeptide FF (NPFF, Phe-Leu-Phe-Gln,Pro-Gln,Arg,Phe-NH2), is a mammalian octapeptide that has been shown to attenuate various opiate-induced effects, like antinociception and the development of morphine tolerance and dependence. It is hypothesized that the administration of morphine releases anti-opiates as part of a homeostatic mechanism. As greater quantities of morphine are administered, increasing quantities of anti-opiates are released into the cerebral spinal fluid. As a direct consequence mu opioid receptor (MOR) complex is down-regulated, producing progressively higher degrees of agonist subsensitivity (tolerance). The present project will examine the mechanism(s) by which NPFF attenuates morphine-induced tolerance via uncoupling of the G protein and/or altering a shared signaling transduction pathway between NPFF and MOR. Rats will be made tolerant by chronic (13 days) intraventricular infusion of morphine sulfate, via the Alzet 2001 osmotic mini-pumps. Because previous findings have shown that chronic i.c.v. infusion of morphine and NPFF alone were able to down-regulate MOR density, the present proposal represents an excellent model to further examine the mechanism(s) by which NPFF attenuates morphine tolerance in spinal cord and discrete brain regions (Cerebral Cortex, Striatum, and Thalamus) that are associated with opiate tolerance. To test this hypothesis, studies will be conducted to test the chronic effects of NPFF on morphine tolerance as measured at several indices related to the MOR signaling transduction pathway (GTP-gamma-S activity, cAMP levels, protein kinases A and C activities). Additional experiments will determine if NPFF modulation at the MOR receptor density is associated with changes at the transcriptional level and/or expression of MOR and NPFF receptor protein. These findings are expected to delineate the mechanism(s) by which NPFF attenuates morphine tolerance by providing a clearer understanding as to where the interaction is occurring within the signaling transduction pathway of the MOR system.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 阿片类药物耐受性的根本机制仍有待阐明。 神经肽 FF (NPFF、Phe-Leu-Phe-Gln、Pro-Gln、Arg、Phe-NH2) 是一种哺乳动物八肽，已被证明可以减弱各种阿片类药物引起的作用，如镇痛和吗啡耐受性和依赖性的发展。 据推测，吗啡的施用会释放抗阿片类药物，作为体内平衡机制的一部分。 随着吗啡给药量的增加，越来越多的抗阿片类药物被释放到脑脊液中。直接结果是 mu 阿片受体 (MOR) 复合物下调，产生逐渐升高的激动剂亚敏感性（耐受性）。本项目将研究 NPFF 通过解偶联 G 蛋白和/或改变 NPFF 与 MOR 之间共享的信号转导途径来减弱吗啡诱导的耐受性的机制。 通过 Alzet 2001 微型渗透泵向脑室内长期（13 天）输注硫酸吗啡，使大鼠产生耐受性。 因为之前的研究结果表明，慢性 i.c.v.单独输注吗啡和 NPFF 能够下调 MOR 密度，目前的建议代表了一个很好的模型，可以进一步研究 NPFF 减弱与阿片耐受性相关的脊髓和离散大脑区域（大脑皮层、纹状体和丘脑）吗啡耐受性的机制。 为了检验这一假设，将进行研究来测试 NPFF 对吗啡耐受的慢性影响，测量与 MOR 信号转导途径相关的几个指标（GTP-gamma-S 活性、cAMP 水平、蛋白激酶 A 和 C 活性）。 其他实验将确定 MOR 受体密度的 NPFF 调节是否与转录水平和/或 MOR 和 NPFF 受体蛋白表达的变化相关。这些发现有望通过提供对 MOR 系统信号转导途径中相互作用发生位置的更清晰的了解来描述 NPFF 减弱吗啡耐受的机制。