Chronic Morphine: Regulation of Ion Conductances

长期使用吗啡会导致对该药物的耐受性和依赖性。细胞耐受的一种机制是阿片受体从这样的效应中解耦，即需要更大的受体占用来获得给定的反应。这种解耦机制已经用效应器进行了研究，包括；钾、钙电导与腺苷酸环化酶的抑制作用。急性阿片类药物脱敏也有类似的现象。急性脱敏被认为至少涉及两个相互关联的过程，通过抑制依赖机制的受体解偶联和通过内化机制从质膜上去除受体。与更持久的耐受性不同，急性脱敏在几分钟内是可逆的，因此更容易在体外研究。本提案的一个目标是定义介导急性阿片类药物脱敏的启动和恢复的事件。这个目标有两个部分，一个是表征急性脱敏和确定受体内化在这一过程中的作用。鉴于受体运输是受体调节的一种重要形式，第二个目标是表征慢性吗啡治疗如何改变阿片受体的脱敏和内化。随着对介导脱敏和内化的事件的更好理解，导致长期耐受性的过程可能更容易确定。第二个目标是确定突触后细胞对慢性阿片类药物治疗的适应性。这些适应与阿片类药物的初始作用相反，即使在吗啡持续存在的情况下也能获得正常功能。因此，适应性机制是一种重要的容忍形式的基础。两种细胞类型将被检查在蓝斑的神经元和中间神经元的VTA。阿片类药物在这些领域的作用有广泛的知识，然而，尚未提出孤立研究突触后适应机制的鉴定和表征。了解戒断吗啡过程中离子通道调节的变化可能有助于制定更有效的预防药物复发的方案。

Chronic use of morphine results in tolerance to and dependence on the drug. One mechanism underlying cellular tolerance is an uncoupling of the opioid receptor from effects such that greater receptor occupancy is required to obtain a given response. This uncoupling mechanism has been studied using effectors that include; potassium and calcium conductances and the inhibition of adenylyl cyclase. A similar phenomenon is observed with acute opioid desensitization. Acute desensitization is thought to involve at least two linked processes, receptor uncoupling through an arresting dependent mechanism and removal of receptors from the plasma membrane through an internalization mechanism. Unlike more protracted forms of tolerance, acute desensitization is reversible within minutes and therefore easier to study in vitro. One goal of this proposal is to define the events that mediate the initiation and recovery from acute opioid desensitization. This goal has two parts, one is to characterize acute desensitization and determine the role of receptor internalization in that process. Given that receptor trafficking is an important form of receptor regulation, the second goal is to characterize how chronic morphine treatment alters desensitization and internalization of the opioid receptor. With a better understanding of the events that mediate desensitization and internalization the processes leading to long term tolerance may be more easily identified. The second goal is to identify post-synaptic cellular adaptations to chronic opioid treatment. These adaptations oppose the initial effect of opioid such that normal function is attained even in the continued presence of morphine. Thus adaptive mechanisms underlie an important form of tolerance. Two cell types will be examined the neurons in the locus coeruleus and interneurons of the VTA. There is an extensive knowledge of opioid actions in these areas, however, the identification and characterization of a post-synaptic adaptive mechanism studied in isolation has yet to be presented. Knowledge of alterations in regulation of ion channels during withdrawal form morphine may help in the development of more efficient protocols for the prevention of relapse to drug use.