A Novel Assay to Improve Translation in Analgesic Drug Development

改善镇痛药物开发转化的新方法

基本信息

批准号：
10726834
负责人：
Sidney S Negus
金额：
$ 24.4万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10726834
关键词：
Abdomen Absence of pain sensation Acute Acute Pain Address Affect Analgesics Animals Behavior Behavioral Biological Biological Assay Characteristics Clinical Collaborations Complex Cutaneous Data Data Collection Depressed mood Development Diagnosis Diazepam Disease Disease model Dose Environment Evaluation Experimental Designs Face Female Floor Foundations Freund&apos s Adjuvant Funding General anesthetic drugs Genes Goals Helping to End Addiction Long-term Human Inbred ICR Mice Inbred Strain Institution Intestines Intraperitoneal Injections Ketoprofen Lactic acid Laparotomy Lithium Chloride Local Anesthetics Locomotion Measures Mental Depression Modeling Monitor Mononeuropathies Morphine Motor Activity Movement Mus Non-Steroidal Anti-Inflammatory Agents Opioid agonist Pain Pain Measurement Pain management Pharmaceutical Preparations Phase Pre-Clinical Model Procedures Reflex action Resistance Series Sickle Cell Anemia Stimulus Sum Surgical incisions Translations United States National Institutes of Health Universities Validation Visceral Visceral pain Withdrawal chronic pain clinical effect clinically relevant cohort drug development drug discovery efficacy testing feeding forest functional disability improved inflammatory pain male mechanical stimulus motor impairment mu opioid receptors nerve injury non-opioid analgesic novel opioid abuse opioid epidemic opioid mortality pain model pre-clinical response restoration scale up sedative sex spared nerve therapeutic candidate

项目摘要

Project Summary This new R61/R33 application responds to NOT-NS-22-095: “Development and Validation of Pain-Related Models and Endpoints to Facilitate Non-Addictive Analgesic Discovery.” In 2017, the National Institutes of Health launched the HEAL initiative, and one major goal of this initiative has been to develop new, non-addicting analgesics. Analgesic drug discovery depends on preclinical models of pain and analgesia for early-stage evaluation of candidate therapeutics, but conventional models that rely on reflex-withdrawal responses elicited by thermal or mechanical stimuli have significant deficits in face and predictive validity. To address these deficits, we have spent more than a decade developing and refining novel behavioral endpoints that focus on pain-related depression of normal behavior. Assays of pain-depresse behavior improve face validity because behavioral depression and functional impairment are cardinal signs of pain diagnosis, and restoration of normal function and behavior is often a major goal of pain treatment. These assays also significantly improve predictive validity by eliminating false-positive effects with drugs that produce motor impairment. This application seeks funding for further validation of a new procedure for use in mice that measures unconditioned locomotor activity in a complex environment as a new type of assay for pain-depressed behavior. Preliminary data suggest that the procedure elicits high and replicable baseline behavior, reliable depression by an acute visceral pain stimulus, and reversal of pain effects by clinically effective analgesics as positive controls but not by two prominent classes of non-analgesics as negative controls. The procedure also has attributes to promote replicability of results, efficiency of experimental design, assessment of sex as a biological variable, and quantitative objectivity of data collection. Proposed studies for further validation would proceed in two phases. In the first R61 phase (Year 1), we propose further studies to meet three milestones. (1) Further validate our procedure with additional positive and negative controls against our visceral acute pain model. (2) Evaluate selectivity of drug effects to restore behavioral depression by acute pain in comparison to behavioral depression by a non-pain treatment (lithium chloride). (3) Evaluate sensitivity of behavioral endpoints to models of more sustained cutaneous and visceral inflammatory pain (intraplantar complete Freund’s adjuvant, Ipl CFA; post-surgical abdominal-incision, AI). In the second R33 phase (Years 2-3), we propose to collaborate with colleagues at VCU and Wake Forest University to scale up and extend the model in three ways. (1) Extend from ICR outbred mice to an inbred strain commonly used to generate gene-altered mice (C57BL/6J). (2) Extend to three additional disease models of chronic pain (mononeuropathy pain using spared nerve injury, SNI; irritable bowel disease, IBD; sickle-cell anemia, SCA). (3) Evaluate independent replication of key results at a partner academic institution (Wake Forest University). Successful completion of the project would provide a comprehensive empirical foundation for broad use of this procedure in efforts to discover non-opioid non-addicting analgesic drugs.

项目概要这个新的 R61/R33 应用程序响应 NOT-NS-22-095：“疼痛相关药物的开发和验证” 促进非成瘾镇痛药发现的模型和终点。”2017 年，美国国立卫生研究院发起了 HEAL 计划，该计划的一个主要目标是开发新的、不成瘾的镇痛药物的发现取决于早期疼痛和镇痛的临床前模型。评估候选疗法，但依赖反射撤回反应的传统模型引发通过热或机械刺激在面部和预测有效性方面存在显着缺陷。我们花了十多年的时间开发和完善专注于疼痛相关的新颖行为终点对正常行为的抑制可以提高表面效度，因为行为。抑郁和功能障碍是疼痛诊断和恢复正常功能的主要标志行为通常是疼痛治疗的主要目标，这些检测也显着提高了预测的有效性。通过消除产生运动障碍的药物的假阳性效应该申请寻求资金。进一步验证用于小鼠的新程序，该程序可测量小鼠的无条件运动活动复杂环境作为一种新型的疼痛抑郁行为检测方法。程序引发高且可复制的基线行为，通过急性内脏疼痛刺激产生可靠的抑郁，临床上有效的镇痛药作为阳性对照可逆转疼痛效应，但两个主要类别则不能逆转疼痛效应该程序还具有促进结果可重复性的特性，实验设计的效率、作为生物变量的性别评估以及数据的定量客观性进一步验证的拟议研究将在第一个 R61 阶段（第一年）进行。我们进一步提出研究以实现三个里程碑（1）以额外的积极作用进一步验证我们的程序。和针对我们的内脏急性疼痛模型的阴性对照（2）评估恢复药物作用的选择性。急性疼痛引起的行为抑郁与非疼痛治疗（锂盐）引起的行为抑郁的比较 (3) 评估行为终点对更持续的皮肤和内脏模型的敏感性炎症性疼痛（足底内完全弗氏佐剂，Ipl CFA；术后腹部切口，AI）。第二个 R33 阶段（第 2-3 年），我们建议与 VCU 和维克森林大学的同事合作大学通过三种方式扩大和扩展该模型（1）从 ICR 远交小鼠扩展到近交系小鼠。通常用于生成基因改变的小鼠 (C57BL/6J) (2) 扩展到另外三种疾病模型。慢性疼痛（由幸免神经损伤引起的单神经病疼痛，SNI；肠易激病，IBD；镰状细胞病 (3) 评估合作伙伴学术机构（维克森林大学）的关键结果的独立复制。大学）的成功完成将为广泛的研究提供全面的实证基础。使用该程序来努力发现非阿片类非成瘾性镇痛药物。