MOR PHosphorylation in Opiod Tolerance and Dependence

阿片类药物耐受性和依赖性中的 MOR 磷酸化

• 批准号: 7217261
• 负责人: Jia Bei Wang
• 金额: $ 12.06万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7217261
• 关键词: Absence of pain sensation; Acute; Agonist; Analgesics; Animal Model; Animals; Biological; Brain; Brain region; Cells; Chinese Hamster Ovary Cell; Class; Condition; Data; Dependence; Development; Dimerization; Down-Regulation; Drug Addiction; Drug abuse; Elements; Endocytosis; G-Protein-Coupled Receptors; GTP-Binding Proteins; Gene Targeting; Genetic; Goals; Heterodimerization; In Vitro; Knock-in Mouse; Ligand Binding; Ligands; Methodology; Modeling; Molecular; Molecular Target; Morphine; Mus; Mutant Strains Mice; Neurons; Neurosciences; Numbers; Opiates; Opioid; Opioid Analgesics; Opioid Receptor; Opium; Pain; Pattern; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Phosphotransferases; Physical Dependence; Process; Property; Range; Rattus; Research; Role; Signal Transduction; Spinal Ganglia; System; Technology; Testing; Thalamic structure; Thinking; Threonine; Tissues; Training; Variant; base; career; cell type; delta opioid receptor; desensitization; design; dimer; in vivo; mouse model; mu opioid receptors; mutant; receptor; receptor recycling; research and development; research study

DESCRIPTION (provided by applicant): To understand the biological basis of drug addiction, genetics and neuroscience are two very important elements. Towards this direction, the Pl's research development and training goals are to pursue the development and application of new methodologies based on gene targeting technology and in vivo animal models. In addition, drug abuse research related educational and severice activities have been incorporated into the proposal to further enhance Pl's career development. Agonist-induced opioid receptor phosphorylation is believed to be an important receptor regulatory process that promotes acute receptor desensitization, triggers internalization and recycling of the receptors, and participates the development of tolerance. However, this has not been demonstrated in neuronal systems and whole animals. Therefore, the proposed research plan is aimed to test the hypothesis that MOR phosphorylation is agonist-dependent as well as region or cell specific, and that the receptor's microconformation and cellular signaling components influence the extent of phosphorylation and the development of differential tolerance and dependence in vivo. Using primary culture of DRG neurons as a model, the PI proposes to examine the MOR phosphorylation pattern in DRG neuron and to evaluate its contribution to desensitization in and other receptor regulatory processes by using phosphorylation-deficient mutant receptor. The PI also proposes to determine the effect of receptor dimerization on MOR phosphorylation, exploring the possible contributions of receptor dimerization to the potential regional variation in receptor phosphorylation and the development of opioid tolerance. The PI further proposes to test the hypothesis in vivo by modifying the MOR phosphorylation status in animal through generating MOR phosphorylation-deficient mutant mice using a knock-in approach. A significance of the proposal is that the study is designed to understand the mechanism of opioid action in a physiologically relevant setting.

描述（由申请人提供）： 要了解药物成瘾的生物学基础，遗传学和神经科学是两个非常重要的因素。朝着这个方向，PI的研究开发和培训目标是追求基于基因靶向技术和体内动物模型的新方法的开发和应用。此外，有关药物滥用研究的教育及服务活动亦已纳入建议内，以进一步加强私人执业律师的职业发展。激动剂诱导的阿片受体磷酸化被认为是一个重要的受体调节过程，其促进急性受体脱敏，触发受体的内化和再循环，并参与耐受的形成。然而，这尚未在神经元系统和整个动物中得到证实。因此，提出的研究计划旨在检验以下假设：莫尔磷酸化是激动剂依赖性的以及区域或细胞特异性的，并且受体的微构象和细胞信号传导组分影响磷酸化的程度以及体内差异耐受性和依赖性的发展。使用DRG神经元的原代培养物作为模型，PI建议通过使用磷酸化缺陷突变受体来检查DRG神经元中的莫尔磷酸化模式并评价其对脱敏和其他受体调节过程的贡献。PI还建议确定受体二聚化对莫尔磷酸化的影响，探索受体二聚化对受体磷酸化的潜在区域变化和阿片类耐受性发展的可能贡献。PI进一步提出通过使用敲入方法产生莫尔磷酸化缺陷突变小鼠，通过改变动物中的莫尔磷酸化状态，在体内检验该假设。该提案的一个重要意义在于，该研究旨在了解阿片类药物在生理相关环境中的作用机制。