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）：文献和我们实验室的证据表明 PKC 与吗啡耐受机制有关。很明显，其作用随着吗啡耐受水平和持续时间的不同而变化。其在对其他阿片类药物耐受中的作用尚未得到详细研究。 PKC 相对于其他神经元成分的重要性尚未明确。本申请中提出的工作的总体目标是开展一项涉及细胞水平电生理技术（布里斯托大学）和全动物研究（VCU）的协作、全面的研究，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。该研究的另一个重要目标是阐明 PKC 与其他细胞蛋白（如 PKA、视紫红质抑制蛋白、GRK 等）在阿片类药物耐受性中的相对重要性。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。两个小组之间密切且持续的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。这种结果的立即交换将直接影响在不同集成水平上工作的其他实验室的下一个实验的设计。该项目的具体目标是检验以下假设：(1) PKC 在急性中度吗啡耐受中起主导作用，PKA 与 PKC 一起参与慢性较高水平的吗啡耐受，(2) 对 mu 阿片受体具有较高功效的阿片类药物在 MOR 处产生非 PKC 依赖性脱敏，并且整个动物对这些药物的耐受性较低 PKC 抑制剂很容易逆转这种现象，(3) GRK、磷酸酶和 Gq 偶联受体在某些阿片类药物耐受中发挥作用，(4) 突触前位点有助于小鼠的 MOR 脱敏和阿片类药物耐受。当人们认为对阿片类药物的耐受性限制了它们在治疗患有慢性疼痛的癌症患者等患者时，这项研究与公共卫生的相关性就受到了重视。如果我们要缓解这个问题，我们需要了解耐受机制。如果我们要解决药物滥用造成的巨大健康问题，阐明耐受性和依赖性的机制也至关重要。