Pain relief: receptor dynamics at the single molecule level

慢性疼痛不再仅仅被认为是一种症状，但由于复杂和难以理解的原因，它往往会自我延续，并成为一种疾病。在许多治疗方法的疼痛管理，镇痛药物治疗继续发挥核心作用。纯阿片类激动剂如吗啡仍然是疼痛药物治疗的金标准，然而吗啡治疗的毒性限制了其长期适用性。迫切需要更好的方法来了解如何提高阿片类药物的耐受性并预测提供哪种镇痛药组合。值得注意的是，尽管吗啡与内源性阿片受体靶向相同的阿片受体（mu opioid receptor， MOR），但它在细胞表面触发自由受体再生的机制不同。在吗啡的刺激下，MORs不会经历通常的内化，这是受体再生的第一步，这一点已经得到了令人信服的证实。鸡尾酒药物诱导的MOR内化率与NMD A受体、DOR和/或β -抑制素的动态之间的相关性将为鸡尾酒的效力提供准确的测定方法。为了观察这些耦合动力学，我们将制作实时的分子电影，以响应对OR和NMDA受体的各种刺激组合。这将使用量子点标签和视频速率显微镜来完成。我们将使用最简单的模型生物系统，提供生物物理反应和已知临床结果之间的相关性。

Chronic pain is no longer considered solely a symptom, but for complex and poorly understood reasons, is often self perpetuating and becomes like a disease unto itself. Among many therapeutic approaches to pain management, analgesic drug therapy continues to play a central role. Pure opioid agonists such as morphine remain the gold standard in pain pharmacotherapy, however toxicity of morphine therapy has limited its long term applicability. Better ways to understand how to improve tolerability of opioids and to predict which combinations of analgesics to offer, are urgently needed. Significantly, although morphine targets the same opioid receptor (mu opioid receptor, MOR) as endogenous opioids, it does not trigger the same mechanism for regeneration of free receptor at the cell's surface. It has been convincingly established that upon stimulation by morphine, MORs do not undergo the usual internalization, which is the first step in receptor regeneration. A drug cocktail induced correlation between the internalization rate of MOR and the dynamics of the NMD A receptor, DOR and/or beta-arrestin will provide an accurate assay for the potency of the cocktail. To observe these coupled dynamics, we will make real time molecular movies of the trafficking of ORs in response to various combinations of stimuli to OR and to the NMDA receptors. This will be accomplished using quantum dot labels and video-rate microscopy. We will use the simplest model biological system that provides correlation between biophysical response and known clinical outcome.