Chronic Morphine: Regulation of Ion Conductances

描述（申请人提供）：mu -阿片受体广泛分布于中枢和周围神经系统，激活后具有多种作用，包括；呼吸抑制，奖赏通路激活，正常胃肠运动中断和镇痛。长期服用阿片类药物导致反应（耐受性）下降，其程度取决于激动剂和所研究的措施。阿片类药物的镇痛耐受性限制了治疗效果。另一方面，肠道耐受性的发展是缓慢的。在细胞和行为水平上测量的耐受性之间的联系涉及两种一般机制，一种涉及受体/效应器耦合的减少，另一种来自抵消阿片样物质信号的稳态适应。这两种机制都是由激动剂/受体结合引发的，并有助于行为耐受。一个可重复和强大的测量阿片作用在单个细胞是急性脱敏。这是细胞耐受途径的初始适应性步骤

DESCRIPTION (provided by applicant): 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. On the other hand, the development of tolerance in the gut is slow. The link between tolerance measured at the cellular and behavioral levels involves two general mechanisms, one involving a reduction of the receptor/effector coupling and the second results from homeostatic adaptations that counteract opioid signaling. Both mechanisms are initiated by agonist/receptor binding and contribute to behavioral tolerance. One repeatable and robust measure of opioid action in single cells is acute desensitization. This is an initial adaptive step in the pathway to cellular tolerance and is the subject of intense investigation. Most emphasis has centered on a model involving (1) agonist occupancy, (2) receptor phosphorylation by a G- protein Receptor Kinase and (3) arrestin binding. This proposal will study mu- opioid receptors directly using a kinetic approach. Experiments will test the hypothesis that opioid receptor desensitization results from an agonist dependent change in receptor conformation that has high affinity for agonist and is less functional. The experiments will go on to determine how this agonist dependent transition of the receptor is changed following chronic treatment of animals with morphine. The recognition and characterization of the high affinity conformation is a necessary step in developing new approaches to control the development of tolerance to opioids. PUBLIC HEALTH RELEVANCE: Opioids are used clinically for the treatment of acute and chronic pain. The development of tolerance is a limitation of these compounds. The results of this study will define the earliest agonist/receptor-dependent processes. Knowledge of these early events with acute application of agonists as well as the change in regulation following chronic treatment will facilitate the development of protocols for safe and effective treatment of pain.