Chronic morphine: Regulation of ion conductances

项目总结 MU-阿片受体广泛分布于中枢和外周神经 系统和激活时有多种动作，包括：按下 呼吸，奖赏通路的激活，正常 胃肠动力和止痛。长期服用阿片类药物的结果 在反应(耐受性)的下降中，其程度取决于 激动剂和正在研究的措施。阿片类药物止痛耐受限度 治疗效果。受体的初始激活和 长期耐受性的发展是深入研究的主题，而且 依赖于多种机制。 在单个细胞上测量的阿片类药物作用的一个可重复和稳健的衡量标准是 急性脱敏。这被认为是该途径的一个初步适应步骤。 到细胞耐受性。脱敏的研究主要集中在(1)激动剂 占有率(2)受体磷酸化(3)arrestin结合和(4)受体 内部化。通过检查受阻于磷酸化的受体 提案将确定脱敏和发展之间的联系 长期容忍。有两种可能的结果。其一，这一块 脱敏扰乱长期耐受性的发展 细胞水平。第二，脱敏的阻碍导致持续的 增强细胞和突触内环境平衡机制的信号 抑制受体持续激活的水平。 这项研究的结果将解决围绕着 一种重要的治疗问题的机制是使用 阿片类药物作为镇痛剂。

PROJECT SUMMARY Mu-opioid receptors are widely distributed in the central and peripheral nervous system and upon activation have manifold actions including; depression of respiration, activation of the reward pathway, disruption of normal gastrointestinal motility and analgesia. Chronic administration of opioids results in a decline in the response (tolerance) the degree of which differs depending on the agonist and the measure under study. Analgesic tolerance to opioids limits the therapeutic efficacy. The link between the initial activation of receptors and the development of long-term tolerance is the subject of intense study and is dependent on multiple mechanisms. One repeatable and robust measure of opioid action measured on single cells is acute desensitization. This is thought to be an initial adaptive step in the pathway to cellular tolerance. Studies of desensitization have centered on (1) agonist occupancy (2) receptor phosphorylation (3) arrestin binding and (4) receptor internalization. By examining receptors where phosphorylation is blocked this proposal will determine the link between desensitization and the development of long-term tolerance. There are two possible outcomes. One is that the block of desensitization disrupts the development of long-term tolerance measured at the cellular level. The second is that the block of desensitization results in continued signaling that augments homeostatic mechanisms at the cellular and synaptic level that counter the continued activation of receptors. The results from this study will address a long-standing question surrounding the mechanisms that underlie a significant therapeutic problem with the use of opioids as analgesics.