Chronic morphine: Regulation of ion conductances

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mu阿片受体脱敏和内化之间的密切关系。各种各样的阿片类药物具有截然不同的药理特性，在临床上用于治疗各种形式的疼痛以及药物成瘾的管理。慢性基础上常用的激动剂有吗啡、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的贩运，但美沙酮能有效地引起这两个过程。脱敏和内化在阿片类药物耐受性和依赖性发展中的作用一直是一个有争议的主题，并在各种模型系统中进行了研究。然而，对于长期使用这三种常用阿片受体激动剂治疗的动物，其耐受性的发展和表达的潜在差异的研究非常有限。这项工作的目的是在用这些激动剂长期治疗动物后，检查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控的过程，该建议的主要假设是这些过程在慢性治疗后以激动剂特异性方式改变。第一个目标是检查长期使用吗啡、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。第二个目标将研究由脱敏浓度的激动剂诱导的受体内化在用三种激动剂中的每一种进行慢性治疗后是如何改变的。第三个目标将检验受体脱敏和内化是独立事件的假设，并且受体内化和功能重新插入到质膜被慢性激动剂治疗显著改变。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机制，并将其应用于更有效的慢性疼痛和成瘾治疗。

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.