Age-related functional consequences and treatment of pain

年龄相关的功能后果和疼痛的治疗

• 批准号: 9813410
• 负责人: Laurence L. Miller
• 金额: $ 44.4万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9813410
• 关键词: Academic Research Enhancement Awards; Acids; Acute; Adult; Affect; Age; Aging; Agonist; Analgesics; Animal Model; Animals; Antidepressive Agents; Behavior; Behavioral; Behavioral Research; Biomedical Research; Chronic; Clinical; Clinical Treatment; Clinical assessments; Depressed mood; Development; Dimensions; Dopamine; Dopamine Uptake Inhibitors; Dose; Elderly; Electrical Stimulation of the Brain; Environment; Evaluation; Female; Freund' s Adjuvant; Functional disorder; Goals; Impairment; Injections; Intraperitoneal Injections; Knowledge; Lactic acid; Locomotion; Mediating; Mental Depression; Methods; Morphine; Motivation; Norepinephrine; Opioid; Opioid Analgesics; Opioid agonist; Outcome; Pain; Pain Measurement; Pain management; Performance; Pharmaceutical Preparations; Physiological; Play; Population; Procedures; Quality of life; Rattus; Recording of previous events; Research; Research Methodology; Rewards; Rodent; Role; Self Stimulation; Serotonin; Signal Transduction; Stimulus; Students; System; Testing; Treatment Protocols; United States; United States National Institutes of Health; Universities; age related; aged; base; behavioral impairment; clinically relevant; dopamine system; evidence base; experience; feeding; functional disability; graduate student; improved; inhibitor/antagonist; interest; male; mature animal; mesolimbic system; monoamine; morphine administration; motivated behavior; novel strategies; opioid exposure; pain model; pre-clinical; pre-clinical research; reuptake; serotonin transporter; undergraduate student; uptake; young adult

Project Summary Pain-related impairment of daily activities is a problem that impacts the quality of life of older adults. As the United states population ages, the rates of chronic analgesic use to treat pain-related depression of behavior in older adults increases. The magnitude of this problem has resulted in NIH prioritizing research examining how aging influences the experience and treatment of pain. A critical barrier to progress in improving the understanding and treatment of pain-related disruption of behavior in older adults is lack of consistency between clinical assessment of pain and the methods used to assess pain in preclinical research. Our goal is to improve treatment of clinically-relevant pain-related impairment of behavior in older adults by obtaining new knowledge on the role of aging in the expression, mechanisms, and treatment of pain using animal models of pain-related depression of behavior. Our central hypothesis is that pain-related dysfunction of dopamine (DA) systems that are important for motivated behavior is a key mechanism of pain-related depression of behavior in older adults. Our hypothesis is based evidence of age-related decreases in DA system activity, and our studies with adult rodents which found that 1) physiologically relevant pain stimuli depress behaviors that include feeding, locomotion and positively reinforced operant behavior, 2) impaired signaling in mesolimbic DA systems is implicated in pain-related depression of behavior, and 3) clinically effective analgesic drugs such as opioids block and reverse pain-related depression of both behavior and mesolimbic DA activity. Our objectives are to 1) model pain-related depression of behavior in aged male and female rats, 2) examine the role of aging in sensitivity to pain-related behavioral dysfunction, and 3) systematically examine determinants of opioid and monoamine uptake inhibitor effects on pain-related depression of behavior in an animal model of aging. Our outcomes will include 1) development and evaluation of a new approach for studying pain in older model organisms, 2) new knowledge of age-related mechanisms and predictors of the pain experience, 3) new knowledge of pain management strategies in aging, and 4) high impact research experiences for students. The impact of these studies will include new scientific information on age-related differences in the expression and mechanisms of motivational dimensions of pain, and determinants of effects of two classes of drugs, opioids and monoamine uptake inhibitors, on pain-related depression of behavior. Aim 1 will test the hypothesis that aging produces stimulus intensity-dependent changes in sensitivity to pain-related depression of behavior. Aim 2 will test the hypothesis that mu opioid agonist intrinsic efficacy and opioid exposure history are determinants of age-related differences in drug effects on pain-related depression of behavior. Aim 3 will test the hypothesis that age will mediate the potency and efficacy of monoamine reuptake inhibitors in an assay of pain-related depression of behavior.

项目概要 与疼痛相关的日常活动障碍是影响老年人生活质量的一个问题。作为 美国人口老龄化、长期使用镇痛药治疗疼痛相关行为抑郁的比率 老年人增加。这个问题的严重性导致 NIH 优先研究如何解决这个问题 衰老影响疼痛的体验和治疗。改善环境方面取得进展的一个关键障碍 对老年人疼痛相关行为障碍的理解和治疗缺乏一致性 疼痛的临床评估以及临床前研究中用于评估疼痛的方法。我们的目标是改进 通过获取新知识来治疗老年人临床相关的疼痛相关行为障碍 使用疼痛相关动物模型研究衰老在疼痛的表达、机制和治疗中的作用 行为抑郁。我们的中心假设是，与疼痛相关的多巴胺 (DA) 系统功能障碍 对动机行为很重要，是老年人疼痛相关行为抑郁的关键机制。 我们的假设基于 DA 系统活性与年龄相关的减少的证据，以及我们对成人的研究 啮齿类动物发现：1）生理相关的疼痛刺激会抑制行为，包括进食、 运动和积极强化的操作行为，2) 中脑边缘 DA 系统中的信号传导受损 与疼痛相关的行为抑郁有关，以及 3) 临床上有效的镇痛药物，如阿片类药物阻滞 并逆转与疼痛相关的行为和中脑边缘 DA 活动的抑制。我们的目标是 1) 建模 老年雄性和雌性大鼠与疼痛相关的行为抑郁，2) 检查衰老在对疼痛的敏感性中的作用 疼痛相关的行为功能障碍，3) 系统地检查阿片类药物和单胺的决定因素 摄取抑制剂对衰老动物模型中与疼痛相关的行为抑郁的影响。我们的成果将 包括 1) 开发和评估一种研究旧模型生物体疼痛的新方法，2) 新方法 年龄相关机制和疼痛体验预测因素的知识，3）疼痛的新知识 老龄化管理策略，4) 为学生提供高影响力的研究经验。这些的影响 研究将包括关于与年龄相关的表达和机制差异的新科学信息 疼痛的动机维度以及两类药物（阿片类药物和单胺）作用的决定因素 摄取抑制剂，对与疼痛相关的行为抑郁。目标 1 将检验衰老产生的假设 对疼痛相关行为抑郁的敏感性发生刺激强度依赖性变化。目标 2 将测试 假设 mu 阿片激动剂内在功效和阿片类药物暴露史是年龄相关的决定因素 药物对疼痛相关行为抑郁的影响存在差异。目标 3 将检验年龄会影响这一假设 在疼痛相关抑郁的测定中介导单胺再摄取抑制剂的效力和功效 行为。