Chronic morphine: Regulation of ion conductances

慢性吗啡：离子电导的调节

• 批准号: 7665369
• 负责人: JOHN T WILLIAMS
• 金额: $ 26.41万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7665369
• 关键词: Acute; Address; Affect; Agonist; Animals; Biological Models; Buprenorphine; Cell membrane; Chronic; Clinic; Dependence; Development; Drug Addiction; Event; Goals; Human; Ions; Kinetics; Knowledge; Methadone; Morphine; Neurons; Opioid; Opioid Receptor; Pain; Pain management; Population; Process; Property; Rattus; Recovery; Recycling; Regulation; Relative (related person); Role; Series; Signal Transduction; Speed; Testing; Tissues; Transgenic Mice; Up-Regulation; Work; addiction; base; chronic pain; clinically significant; desensitization; effective therapy; locus ceruleus structure; mu opioid receptors; receptor; receptor internalization; research study; trafficking

DESCRIPTION (provided by applicant): A close relationship between desensitization and internalization of mu opioid receptors has been proposed based on differential actions of series of agonists. A wide variety of opioids that have dramatically different pharmacological properties are used in the clinic for the treatment of various forms of pain as well as the managment of drug addiction. Agonists that are commonly administered on a chronic basis are morphine, methadone and buprenorphine. Morphine and buprenorphine do not induce marked acute desensitization or trafficking of receptors, but, methadone is efficient at causing both processes. The role that desensitization and internalization have in the development of tolerance and dependence to opioids has been a controversial subject and has been studied in a variety of model systems. There has, however, been only limited study on potential differences in the development and expression of tolerance that result from the chronic treatment of animals with these three commonly used opioid agonists. The goal of this work is to examine both desensitization and internlaization of receptors in neurons after treating animals chronically with each of these agonists. Opioid receptor desensitization and internalization are highly regulated processes in neurons and the primary hypothesis of this proposal is that these processes are altered in an agonist specific way following chronic treatment. The first aim will examine tolerance and the recovery from acute desensitization in animals (rats) treated chronically with morphine, methadone and buprenorphine. The second aim will examine how receptor internalization induced by a desensitizing concentration of agonist is altered following the chronic treatment of animals (transgenic mice) with each of the three agonists. The third aim will test the hypothesis that receptor desensitization and internlaization are separate events and that receptor internalization and functional reinsertion to the plasma membrane is dramatically altered by chronic agonist treatment. By gaining knowledge of the processes that are selectively affected by some agonists and not others, the mechanisms underlying the development of tolerance and dependence may be identified and applied to more effective treatment of chronic pain and addiction.

描述（由申请人提供）：基于一系列激动剂的不同作用，已经提出了μ阿片受体的脱敏和内化之间的密切关系。临床上使用具有显着不同药理特性的多种阿片类药物来治疗各种形式的疼痛以及治疗药物成瘾。通常长期服用的激动剂有吗啡、美沙酮和丁丙诺啡。吗啡和丁丙诺啡不会引起明显的急性脱敏或受体运输，但美沙酮可有效引起这两个过程。脱敏和内化在阿片类药物耐受和依赖性发展中的作用一直是一个有争议的话题，并已在各种模型系统中进行了研究。然而，对于用这三种常用阿片类激动剂对动物进行长期治疗所导致的耐受性发展和表达的潜在差异的研究非常有限。这项工作的目的是检查长期用这些激动剂治疗动物后神经元中受体的脱敏和内化。阿片受体脱敏和内化是神经元中高度调节的过程，该提议的主要假设是这些过程在长期治疗后以激动剂特异性方式发生改变。第一个目标是检查长期接受吗啡、美沙酮和丁丙诺啡治疗的动物（大鼠）的耐受性和急性脱敏的恢复情况。第二个目标将研究在用三种激动剂中的每一种对动物（转基因小鼠）进行长期治疗后，由脱敏浓度的激动剂诱导的受体内化如何改变。第三个目标将检验以下假设：受体脱敏和内化是独立的事件，并且受体内化和功能性重新插入质膜会因长期激动剂治疗而显着改变。通过了解受某些激动剂而非其他激动剂选择性影响的过程，可以确定耐受性和依赖性发展的潜在机制，并将其应用于更有效地治疗慢性疼痛和成瘾。