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: 7465564
• 负责人: William L. Dewey
• 金额: $ 24.75万
• 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/7465564
• 关键词: Acute; Affect; Animals; Arrestin; Arrestins; Chronic; Class; Collaborations; Condition; Cyclic AMP-Dependent Protein Kinases; Daily; Data; Dependence; Development; Drug abuse; Electronic Mail; GRK; Goals; Grant; Health; Investigation; Knockout Mice; Laboratories; Literature; Malignant Neoplasms; Morphine; Mus; Neurons; Opioid; Patients; Personal Satisfaction; 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）：文献和我们的实验室中存在的证据表明PKC参与吗啡耐受机制。很明显，它的作用随吗啡耐受的不同水平和持续时间而变化。它在耐受其他阿片类药物中的作用尚未详细研究。PKC相对于其他神经元成分的重要性尚未得到很好的定义。本申请中提出的工作的总体目标是进行一项涉及细胞水平电生理学技术（布里斯托大学）和整体动物研究（VCU）的协作、全面调查，以阐明PKC是否以及如何在吗啡和其他阿片类药物耐受性中发挥关键作用。本研究的另一个重要目的是阐明PKC与其他细胞蛋白如PKA、arrestins、GRK等在阿片耐受中的相对重要性。我们建议研究PKC的特定亚型，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。两个小组之间的密切和持续合作将为每个实验室的协调实验设计提供日常输入（电子邮件和数据传输）的机制。这种结果的即时交换将直接影响到另一个实验室在不同集成水平上工作的下一个实验的设计。该项目的具体目的是检验以下假设：（1）PKC在急性中度吗啡耐受中起主要作用，PKA沿着PKC参与慢性较高水平的吗啡耐受，（2）对μ阿片受体具有较高功效的阿片类药物在MORs产生非PKC依赖性脱敏，整个动物对这些药物的耐受不太容易被PKC抑制剂逆转，（3）GRKs、磷酸酶和Gq偶联受体在某些阿片耐受中起作用;（4）突触前位点参与小鼠莫尔脱敏和阿片耐受。当人们认为对阿片类药物的耐受性限制了其在治疗慢性疼痛的癌症患者等患者中的使用时，这项研究与公共卫生的相关性受到赞赏。如果我们要减轻这个问题，我们需要了解宽容的机制。如果我们要解决药物滥用造成的巨大健康问题，我们还必须阐明耐受性和依赖性的机制。