MEMBRANE POTENTIAL AND MORPHINE TOLERANCE

膜电位和吗啡耐受性

• 批准号: 2733492
• 负责人: DAVID A. TAYLOR
• 金额: $ 17.08万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-08-05 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2733492
• 关键词: action potentials; brain stem; densitometry; drug addiction; drug tolerance; electrophysiology; environmental adaptation; guinea pigs; laboratory rat; locus coeruleus; membrane potentials; morphine; myenteric plexus; neurons; neuroregulation; opioid receptor; psychobiology; single cell analysis; species difference; voltage /patch clamp

DESCRIPTION: (Applicant's Abstract) The cellular basis underlying the development of tolerance and dependence following chronic exposure to opioids is not known. Two different hypotheses have emerged based upon data generated using different neuronal populations and different species. One hypothesis ascribes a highly specific alteration in responsiveness to opioids to alterations in the cellular transduction processes using studies conducted in different brain regions of the rat. The other hypothesis is focused on the cellular adaptive mechanisms which lead to a generalized change in responsiveness extending to a variety of both inhibitory and excitatory substances. The cellular basis for this type of heterologous subsensitivity has been shown by this laboratory to reside in a generalized change in cellular membrane properties in a variety of excitable tissues. Work in this laboratory relative to the role of such adaptive changes in responsiveness have investigated the development of tolerance following chronic opioid treatment using the myenteric plexus and nucleus tractus solitarius of the guinea pig as model systems. The underlying differences which may be responsible for these disparatate (sic) hypotheses could either reside in the neuronal populations being examined or in the species in which the tolerance is being produced. The experiments proposed will employ mainly electrophysiological techniques including intracellular and patch clamp recording from neurons in brain slices from control and animals chronically treated with morphine. The hypothesis to be tested is that the expression of tolerance following chronic opioid treatment differs between the guinea pig and 4 the rat as a result of basic differences in the cellular mechanism of adaptation employed by these two species. To test this hypothesis, the following specific aims will be addressed: 1) To determine if the guinea pig LC displays nonspecific tolerance extending to non-opioid inhibitory agonists; 2) To determine if the rat nTS displays tolerance that is specific for mu-opioid agonists; and 3) To investigate the cellular mechanisms which underlie tolerance in the guinea pig LC and nTS and the rat nTS. The outcome of these experiments will enhance our understanding of opioid tolerance and dependence as well as increase our knowledge about the mechanisms of neuronal adaptation.

描述：（申请人的摘要） 耐受性和依赖性发展的基础细胞基础 长期暴露于阿片类药物后，尚不清楚。 两个不同 基于使用不同神经元产生的数据出现了假设 种群和不同的物种。 一个假设归因于高度 对阿片类药物对改变的反应性的具体改变 使用在不同大脑中进行的研究的细胞转导过程 大鼠的区域。 另一个假设集中于细胞 自适应机制，导致响应能力的普遍变化 扩展到各种抑制性和兴奋性物质。 这 已经显示了这种类型的异敏性的细胞基础 该实验室居住在细胞膜的广义变化中 多种可激发组织中的特性。 在这个实验室工作 相对于这种适应性变化在响应性中的作用 研究了慢性阿片类药物治疗后耐受性的发展 使用豚鼠的骨髓神经丛和核Tractus solitarius 作为模型系统。 可能负责的基本差异 这些不同的（SIC）假设可以存在于神经元中 被检查的种群或在公差所在的物种中 生产。 提出的实验将主要采用电生理学 包括来自神经元的细胞内和斑块夹的技术 对照和动物的大脑切片用吗啡治疗。 要检验的假设是耐受性的表达 慢性阿片类药物治疗在豚鼠和4大鼠之间有所不同 所采用的细胞机制基本差异的结果 通过这两个物种。 为了检验这一假设，以下特定目标 将解决：1）确定豚鼠LC是否显示 非特异性耐受性延伸至非阿片类药物抑制性激动剂； 2）到 确定大鼠NTS是否显示针对Mu-Apoid特定的公差 激动剂； 3）研究基础的细胞机制 豚鼠LC和NTS以及大鼠NTS的耐受性。 结果 这些实验将增强我们对阿片类药物耐受性的理解和 依赖性以及我们对机制的了解 神经元适应。