Chronic Morphine: Regulation of Ion Conductances

描述（由申请人提供）：μ-阿片受体广泛分布于中枢和外周神经系统，激活后具有多种作用，包括：抑制呼吸、激活奖赏途径、破坏正常胃肠道运动和镇痛。类阿片长期给药导致反应（耐受性）下降，其程度因激动剂和所研究的措施而异。对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。在细胞水平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/效应器偶联的减少，第二种来自抵消阿片信号传导的稳态适应。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。阿片类药物在单细胞中作用的一种可重复和可靠的测量方法是急性脱敏。这是细胞耐受途径中的初始适应性步骤， 这是一个正在深入调查的问题。大多数重点集中在涉及（1）激动剂占据，（2）G蛋白受体激酶引起的受体磷酸化和（3）抑制蛋白结合的模型上。这项建议将直接使用动力学方法研究μ阿片受体。实验将检验阿片样物质受体脱敏是由受体构象的激动剂依赖性变化引起的假设，所述受体构象对激动剂具有高亲和力并且功能较弱。实验将继续确定这种受体的激动剂依赖性转换在用吗啡长期治疗动物后如何改变。高亲和力构象的识别和表征是开发新方法来控制阿片类药物耐受性发展的必要步骤。

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.