The Role of Protein Kinase C in Opioid Tolerance

蛋白激酶 C 在阿片类药物耐受中的作用

• 批准号: 7652489
• 负责人: William L. Dewey
• 金额: $ 24.64万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7652489
• 关键词: Acute; Affect; Animals; Arrestins; Chronic; Collaborations; Cyclic AMP-Dependent Protein Kinases; Data; Dependence; Development; Drug abuse; Electronic Mail; GRK; Goals; Grant; Health; Investigation; Knockout Mice; Laboratories; Literature; Malignant Neoplasms; Morphine; Mus; Neurons; Opioid; Patients; Phosphoric Monoester Hydrolases; Phosphotransferases; Play; Protein Isoforms; Protein Kinase C; Proteins; Public Health; Relative (related person); Research; Role; Site; Small Interfering RNA; Staging; Techniques; Testing; Time; Universities; Work; chronic pain; desensitization; design; in vivo; inhibitor/antagonist; mu opioid receptors; presynaptic; receptor coupling; research study

DESCRIPTION (provided by applicant): Evidence exists in the literature and from our laboratories to implicate PKC in the mechanism of morphine tolerance. It is clear that its role varies with different levels and durations of morphine tolerance. Its role in tolerance to other opioids has not been studied in detail. The importance of PKC in relation to other neuronal constituents has not been well defined. The overall goal of the work proposed in this application is to carry out a collaborative, comprehensive investigation involving electrophysiological techniques at the cellular level (University of Bristol) with whole animal studies (VCU) to elucidate not only if but also how PKC plays a pivotal role in morphine and other opioid tolerance. Another important goal of the research is to elucidate the relative importance of PKC to other cellular proteins such as PKA, arrestins, GRK etc in opioid tolerance. We propose to study the specific isoforms of PKC and to use knockout mice and siRNA techniques in both laboratories to elucidate the mechanisms involved. Close and continual collaboration between the two groups will provide a mechanism for daily input (email and data transfer) into the design of coordinated experiments in each laboratory. This immediate interchange of result will directly affect the design of the next experiment in the other laboratory working at a different level of integration. The specific aims of the project are to test the hypotheses that (1) PKC plays the predominant role in acute moderate morphine tolerance, and that PKA along with PKC are involved in chronic higher levels of morphine tolerance,(2) that opioids with a higher efficacy at mu opioid receptors produce a non-PKC dependent desensitization at MORs and tolerance to these agents in the whole animal is less easily reversed by PKC inhibitors, (3) GRKs, phosphatases and Gq-coupled receptors play a role in some opioid tolerances and (4) that presynaptic sites contribute to both MOR desensitization and opioid tolerance in mice. The relevance of this research to public health is appreciated when one considers that tolerance to opioids limits their use in treating patients such as those with cancer who have chronic pain. We need to understand the mechanisms of tolerance if we are going to alleviate this problem. Also it is essential that we elucidate the mechanisms of tolerance and dependence if we are going to solve the enormous health problems caused by drug abuse.

描述（由申请人提供）：文献中存在证据，我们的实验室中存在将PKC牵涉到吗啡耐受机制。显然，其作用随吗啡耐受的水平和持续时间而变化。尚未详细研究其在耐受其他阿片类药物中的作用。 PKC与其他神经元成分有关的重要性尚未得到很好的定义。本应用程序提出的工作的总体目标是进行一项协作，全面的研究，涉及整个动物研究（VCU）在细胞水平（布里斯托尔大学）的电生理技术（VCU），以不仅阐明PKC在吗啡和其他阿片类耐受性中扮演关键作用。该研究的另一个重要目标是阐明PKC对阿片类药物耐受性中PKC对其他细胞蛋白的相对重要性。我们建议研究PKC的特定同工型，并在两个实验室中使用基因敲除小鼠和siRNA技术来阐明所涉及的机制。两组之间的紧密和持续的合作将为每个实验室的协调实验设计提供每日输入（电子邮件和数据传输）的机制。结果的这种直接互换将直接影响下一个实验室的下一个实验的设计，以不同的整合水平工作。该项目的具体目的是测试（1）PKC在急性中度中等吗啡耐受性中起主要作用，并且PKA与PKC一起涉及慢性较高的吗啡耐受性，（2）阿片类药物在MU ApeireD的较低效率上产生了较高的依赖性，而这些动物敏感性较高的动物质量依赖于这些动物质量的人群和这些动物质量分别是这些动物质量的分析，这些依赖性的成分是这些动物质量的，这些人的成分是这些人的成分，这些人和较高的效率是这些人的成分，这些人的成分是这些人的成分，这些人和较高的效率是这些人的成分，这些人和较高的效率是这些人的质量构成的，这些人的成分是这些人的成分，这些人的成分是这些人的成分，这些人的成分是这些人的质量和较高的作用。 PKC抑制剂，（3）GRK，磷酸酶和GQ耦合受体很容易逆转在某些阿片类药物耐受性中起作用，并且（4）突触前部位在小鼠中有助于MOR脱敏和阿片类药物耐受性。当人们认为对阿片类药物的耐受性限制了治疗患者（例如患有慢性疼痛的癌症患者）的使用时，这项研究与公共卫生的相关性将受到赞赏。如果我们要缓解这个问题，我们需要了解宽容的机制。同样，如果我们要解决吸毒引起的巨大健康问题，我们必须阐明宽容和依赖机制。