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: 7335966
• 负责人: CARL B GOODMAN
• 金额: $ 5.57万
• 依托单位: FLORIDA AGRICULTURAL AND MECHANICAL UNIV
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7335966
• 关键词: NEUROSCIENCE; SUBPROJECT; MODULATION; MORPHINE; TOLERANCE; NEUROSCIENCE; SUBPROJECT; MODULATION; MORPHINE; TOLERANCE

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NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。阿片耐受性的基本机制仍有待阐明。神经肽FF（NPFF，PHE-LEU-PHE-GLN，Pro-GLN，ARG，PHE-NH2）是一种哺乳动物八肽，已显示出可减弱各种鸦片诱导的作用，例如抗伤害感，例如抗伤害感和吗啡耐受性和依赖性和依赖性。假设吗啡的施用将抗植物释放为稳态机制的一部分。随着增加数量的吗啡，越来越多的抗摄影剂释放到脑脊髓液中。作为直接结果，MU阿片受体（MOR）复合物被下调，产生逐渐更高的激动剂亚敏度（耐受性）。本项目将检查NPFF通过解开G蛋白和/或改变NPFF和MOR之间的共享信号转导途径来减弱吗啡诱导的耐受性的机制。通过Alzet 2001渗透迷你泵，将大鼠通过硫酸吗啡硫酸吗啡的脑室室内输注耐受耐受性。因为以前的发现表明慢性I.C.V.单独的吗啡和NPFF的输注能够下调MOR密度，目前的提案代表了一个出色的模型，可以进一步研究NPFF在脊髓和离散大脑区域（脑皮质，纹状体和丘脑）中降低吗啡耐受性的机制，与阿片不可塑料相关。为了检验这一假设，将进行研究以测试NPFF对吗啡耐受性的慢性影响，如在与MOR信号转导途径（GTP-GAMMA-S活性，CAMP水平，蛋白质激酶A和C活性）相关的几个指数中测量。其他实验将确定在MOR受体密度下的NPFF调制是否与MOR和NPFF受体蛋白的转录水平和/或表达的变化有关。这些发现有望描绘出NPFF通过对MOR系统信号传输途径中的相互作用的何处的何处提供更清晰的理解来减轻吗啡耐受性的机制。