Intrinsic Efficacy as a Determinant of Opioid Effectiveness in Treatment of Pain-Depressed Behavior

项目总结/摘要 疼痛是一个重要的公共卫生问题，不仅与不愉快的主观感觉有关， 伴有减少日常生活正常活动的行为抑郁和功能障碍（例如进食， 步行、工作）和整体生活质量。治疗和管理策略变得稀缺， 目前的药物并不是长期有效的，可能会有一系列的副作用， 使患者难以依从。高效阿片类药物，如吗啡，其结合μ阿片类药物 受体（莫尔）在有效治疗疼痛方面具有历史地位，但由于 副作用和阿片类药物危机虽然应用程序承认这一点，但这一努力忽略了另一条路径 用于开发安全有效的镇痛药：进一步开发低效莫尔激动剂， 足够的功效以产生临床有效的镇痛，并且副作用比高剂量的药物更少和/或更不严重。 有效性莫尔激动剂。拟议的项目旨在利用一种新的和高度灵活的战略， 通过测试一系列芬太尼和纳洛酮（Fent/NTX）混合物精确控制激活莫尔的净功效 和新的莫尔选择性化合物。特别关注的是疼痛抑郁的行为，因为这些都是 临床上可翻译的目的1提出研究攀爬作为疼痛-抑郁行为终点。五 在莫尔下净效力从高到低的Fent/NTX混合物和具有莫尔的三种新型化合物 将在存在和不存在所用腹膜内（IP）乳酸的情况下研究选择性和分级疗效 急性伤害性刺激。目的2提出利用多巴胺受体阻断剂来研究丘脑腹外侧核多巴胺的变化。 体内成像荧光测定技术dLight。这将使用Fent/NTX混合物的子集来完成，以评估 IP乳酸诱导的急性疼痛和疼痛非依赖性神经化学变化。目标3建议进一步 在一系列慢性疼痛研究中，将攀岩作为一种疼痛抑制行为进行研究。单独的小鼠组将 采用足爪切开法建立术后疼痛模型，足底注射完全弗氏佐剂（CFA） 炎性疼痛，反复注射化疗紫杉醇（PAC），和保留神经损伤（SNI）， 神经性疼痛模型。总的来说，拟议的项目旨在研究Fent/NTX混合物的影响 作为研究阿片类药物治疗急性疼痛相关行为抑郁疗效的决定因素的工具 并将为研究这些混合物在慢性疼痛状态下的作用奠定基础， 翻译.

PROJECT SUMMARY/ABSTRACT Pain is a significant public health problem associated not only with unpleasant subjective sensations, but also with behavioral depression and functional impairment that reduce normal activities of daily living (e.g. eating, walking, working) and overall quality of life. Treatment and management strategies have become scarce as current medications have not been effective long-term and may come with a list of side effects that limits their use and make it difficult for patient compliance. High-efficacy opioids such as morphine which bind the mu opioid receptor (MOR) have a historical place for the effective treatment of pain but their use has been limited due to side effects and the opioid crisis. While the application acknowledges this, this effort neglects an alternative path for development of safe and effective analgesics: the further development of low-efficacy MOR agonists with sufficient efficacy to produce clinically effective analgesia with fewer and/or less severe side effects than high- efficacy MOR agonists. The proposed project aims to utilize a novel and highly flexible strategy for selective and precise control of net efficacy to activate MOR by testing a series of fentanyl and naltrexone (Fent/NTX) mixtures and novel MOR selective compounds. Special focus is proposed on pain-depressed behaviors as these are clinically translatable. Aim 1 proposes to study climbing as the pain-depressed behavioral endpoint. Five Fent/NTX mixtures that range from high to low net efficacy at MOR and three novel compounds with MOR selectivity and graded efficacy will be studied in the presence and absence of intraperitoneal (IP) lactic acid used as the acute noxious stimulus. Aim 2 proposes to study dopamine changes in the nucleus accumbens using the in vivo imaging fluorimetry technique dLight. This will be done using a subset of Fent/NTX mixtures to asses acute pain induced by IP lactic acid and pain-independent neurochemical changes. Aim 3 proposes to further study climbing as a pain-depressed behavior in a series of chronic pain studies. Separate groups of mice will receive paw incision to model postsurgical pain, intraplantar complete Freund’s adjuvant (CFA) to model inflammatory pain, repeated injection of the chemotherapy paclitaxel (PAC), and spared nerve injury (SNI) to model neuropathic pain. As a whole, the proposed project aims to investigate the effects of Fent/NTX mixtures as tools to investigate efficacy as a determinant of opioid treatment for acute pain-related behavioral depression and will set the stage to study these mixtures in chronic pain states as a means for better preclinical to clinical translation.