Mechanisms of opioid receptor desensitisation in single neurons

阿片类药物包括吗啡和可待因是已知的最有效的镇痛剂，但它们的效用受到耐受性问题（这是需要增加药物剂量以达到相同的效果）、身体依赖性（特征在于停止使用时的衰弱性戒断综合征）以及成瘾或强迫性药物寻求和使用的限制。更好地了解这些不良反应的机制可能会导致更可接受的止痛药的发展。该项目将增加对神经细胞中发生的初始分子事件的理解，这些事件被认为是阿片类药物耐受性和身体依赖性发展的基础。这些研究将集中在从动物中分离和培养的感觉神经细胞上，这是止痛药物的主要靶点之一。了解这些过程将导致更好的策略，以避免发展的耐受性和身体依赖性的发展。他们还将在分子水平上确定决定为什么一种阿片类药物可能比另一种产生更多耐受性的机制。这一知识可能会导致疼痛缓解药物的发展，不那么容易失去其在慢性疼痛管理的有效性。

Opioid drugs including morphine and codeine are the most effective analgesics known but their utility is limited by problems of tolerance (which is the need for increasing doses of drug to achieve the same effect), physical dependence characterised by a debilitating withdrawal syndrome on cessation of use, and addiction or compulsive drug seeking and use. Better understanding of the mechanisms underlying these adverse processes could lead to the development of more acceptable pain relieving agents. This project will increase understanding of the initial molecular events occurring in nerve cells that are believed to underlie the development of tolerance and physical dependence on opioid drugs. These studies will focus on sensory nerve cells isolated and cultured from animals, which are one of the major targets of pain relieving drugs. Understanding of these processes will lead to development of better strategies to avoid development of tolerance and perhaps physical dependence. They will also identify on a molecular level the mechanisms that determine why one opioid drug may produce more tolerance than another. This knowledge may lead to the development of pain relieving drugs that do not so readily lose their effectiveness in the management of chronic pain.