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

内在功效是阿片类药物治疗疼痛抑郁行为有效性的决定因素

• 批准号: 10389903
• 负责人: Edna J Santos
• 金额: $ 4.04万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10389903
• 关键词: Absence of pain sensation; Acids; Activities of Daily Living; Acute; Acute Pain; Affect; Aftercare; Analgesics; Behavior; Behavioral; Behavioral Model; Binding; Biological Assay; Biosensor; Buprenorphine; Chronic inflammatory pain; Clinic; Clinical; Data; Depressed mood; Development; Diagnostic; Dopamine; Dose; Eating; Effectiveness; Esthesia; Female; Fentanyl; Freund' s Adjuvant; Future; Goals; Human; Impairment; Inbred ICR Mice; Individual; Inflammatory; Injections; Instinct; Laboratories; Lactic acid; Mental Depression; Modeling; Morphine; Mus; Nalbuphine; Naltrexone; Neuropathy; Nucleus Accumbens; Operative Surgical Procedures; Opioid; Opioid Analgesics; Opioid agonist; Paclitaxel; Pain; Pain Research; Pain management; Pharmaceutical Preparations; Play; Plexiglass; Postoperative Pain; Public Health; Quality of life; Reporting; Role; Series; Signal Transduction; Source; Stimulus; Surgical incisions; Techniques; Testing; United States National Institutes of Health; Ventilatory Depression; Veterinary Medicine; Viral Vector; Visceral; Visit; Walking; abuse liability; antagonist; chemotherapy; chronic pain; clinical translation; clinically translatable; compliance behavior; drug action; effective therapy; flexibility; functional disability; in vivo imaging; inflammatory pain; intraperitoneal; male; motor impairment; mu opioid receptors; neglect; nerve injury; neurochemistry; non-opioid analgesic; novel; opioid abuse; opioid epidemic; opioid mortality; pain behavior; pain model; pain relief; painful neuropathy; pre-clinical; pre-clinical research; side effect; single molecule; spared nerve; tool

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.

项目摘要/摘要 疼痛是一个重大的公共卫生问题，不仅与令人不愉快的主观感觉有关 随着行为抑郁和功能障碍，减少日常生活的正常活动（例如饮食， 步行，工作）和整体生活质量。治疗和管理策略已变得稀缺 当前的药物长期没有有效，可能会列出副作用，以限制其 使用并使患者合规难以进行。高效率阿片类药物（例如吗啡）结合MU阿片类药物 接收器（MOR）有一个历史地位可以有效治疗疼痛，但由于 副作用和阿片类药物危机。虽然应用程序确认这一点，但这项工作忽略了另一种道路 为了开发安全有效的镇痛学：与低效率的MOR激动剂的进一步发展 与高 - 相比 功效激动剂。拟议的项目旨在利用一种新颖且高度灵活的策略进行选择性和 通过测试一系列芬太尼和纳曲酮（Fent/NTX）混合物来激活MOR的净效率的精确控制 和新颖的MOR选择性化合物。提出特别关注疼痛抑郁的行为，因为这些行为是 临床翻译。目标1将攀岩作为痛苦抑郁的行为终点的提议。五 Fent/NTX混合物的范围从MOR的高到低净效率以及MOR的三种新型化合物 选择性和分级效率将在存在和不存在腹膜内（IP）乳酸的情况下进行研究 作为急性有害刺激。目标2使用使用该细胞核研究多巴胺变化的建议 体内成像荧光学技术。这将使用芬特/NTX混合物的子集完成 IP乳酸诱导的急性疼痛和无疼痛的神经化学变化。瞄准3个建议进一步 在一系列慢性疼痛研究中，研究将攀爬作为疼痛抑郁的行为。单独的小鼠将 接收PAW切口，以进行术后疼痛模型，全球内弗朗德的可调（CFA） 炎症性疼痛，反复注射化学疗法紫杉醇（PAC）以及免受神经损伤（SNI） 模型神经性疼痛。总体而言，拟议的项目旨在研究芬特/NTX混合物的影响 作为研究效率的工具，作为急性疼痛相关行为抑郁的阿片类药物治疗的确定 并将为在慢性疼痛状态中研究这些混合物的阶段，以此作为更好的临床前临床上的手段 翻译。