Chronic morphine: Regulation of ion conductances

项目摘要 μ-阿片受体广泛分布于中枢和外周神经系统 系统和激活时具有多种作用，包括： 呼吸，奖赏途径的激活，正常的 胃肠蠕动和镇痛。阿片类药物长期给药结果 反应（耐受性）下降，其程度取决于 激动剂和所研究的措施。对阿片类药物的镇痛耐受性限制 治疗效果。受体的初始激活与 长期耐受性的发展是深入研究的主题， 依赖于多种机制。 对单细胞测量的阿片样物质作用的一种可重复且稳健的测量是 急性脱敏。这被认为是该途径中的初始适应步骤 到细胞耐受性。脱敏的研究主要集中在（1）激动剂 占据（2）受体磷酸化（3）抑制蛋白结合和（4）受体 内化通过检测磷酸化被阻断的受体， 建议将确定脱敏和发展之间的联系， 长期的宽容。有两种可能的结果。一个是， 脱敏破坏了长期耐受性的发展， 细胞水平。第二，脱敏的阻碍导致持续的 增强细胞和突触稳态机制的信号传导 抑制受体持续激活的水平。 这项研究的结果将解决围绕 这些机制是使用药物治疗的一个重要问题的基础， 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.