Novel Analgesics for Improved Pain Therapy in Advancing Age

用于改善老年疼痛治疗的新型镇痛药

• 批准号: 8443261
• 负责人: James E Zadina
• 金额: --
• 依托单位: SOUTHEAST LOUISIANA VETERANS HEALTH CARE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8443261
• 关键词: Absence of pain sensation; Acute; Address; Adverse effects; Aging; Agonist; Analgesics; Area; Biological; Brain; Chronic; Degenerative Disorder; Dose; Elderly; Failure; Fracture; Goals; Impaired cognition; Impairment; Inflammation; Inflammatory Response; Injection of therapeutic agent; Injury; Laboratories; Lead; Measures; Memory; Modeling; Morphine; Morphine Receptors; Motor; Opioid; Pain; Pain management; Pathology; Patients; Pharmaceutical Preparations; Population; Rattus; Relative (related person); Respiratory physiology; Rewards; Structure; Testing; Traumatic Brain Injury; Ventilatory Depression; Veterans; War; abstracting; analog; base; behavior change; cognitive function; endogenous opioids; falls; improved; middle age; mild cognitive impairment; morris water maze; motor impairment; neurochemistry; neurogenesis; novel; object recognition; programs; public health relevance

DESCRIPTION (provided by applicant): Project Summary/Abstract Pain is highly prevalent in older adults, but also has a high likelihood of being inadequately treated. Among the reasons for this failure is concern about adverse side effects of currently used analgesics. Older adults, particularly at 85+ years, represent a growing proportion of population, and the declining population of WWII-era veterans is being replaced by veterans surviving more severe injuries than in earlier wars. Thus, there is a strong need to develop new pain treatments with fewer side effects, including those that are particularly problematic for older adults. Opioids acting at the mu (morphine) receptor represent the vast majority of clinically used opioids and remain the most effective at treating moderate to severe pain. However, the use of morphine, and similar compounds, for the management of pain is limited by adverse side effects including respiratory depression, abuse potential, and motor and cognitive impairment. In addition, recent studies have indicated that repeated injection of morphine, for even a few days, can induce glial activation, an inflammatory response that can lead to a "paradoxical" morphine-induced pain. This may be of particular importance in the treatment of pain in patients already vulnerable to inflammation-induced pathologies, including older adults. The goal of this program is to develop novel mu opioid agonists that provide effective analgesia (antinociception) with fewer adverse side effects relative to morphine. The compounds to be tested are analogs based on the structures of endogenous opioids (endomorphins) discovered in our laboratory that have been shown to produce less respiratory depression and reward (abuse potential) than morphine. Many older adults have compromised respiratory function that can be exacerbated by opioid-induced respiratory depression. Impairment of motor coordination can be particularly serious in patients for whom falls and fractures are more likely to occur and with serious consequences. Opioids are also known to impair cognitive function. Older adults, especially those with mild cognitive impairment, degenerative diseases, or traumatic brain injury, may be especially vulnerable to opioid side-effects. A major hypothesis is that these analogs will produce less neuromotor and cognitive impairment in young, middle-aged, and old rats than morphine. This hypothesis will be tested in a rotorod test of motor coordination, the Morris Water Maze test of spatial memory, and the Object Recognition Task for object memory. Doses of morphine that produce the known impairment on these tasks will be matched by equiantinociceptive doses of the endomorphin analogs to provide a valid comparison of the relative analgesia/side-effect ratio. Effects of acute and chronic treatment will be tested. An additional hypothesis is that glial activation and impairment of neurogenesis will be observed in key brain areas after chronic treatment with morphine but not the analogs. Excessive glial activation and impaired neurogenesis have been associated with cognitive impairment in many studies, and it is anticipated that these neurochemical changes will correlate with the behavior changes measured in this project. If successful, the program will provide novel compounds for more effective pain management with fewer side effects than current medications, with particular value for older adults.

描述（由申请人提供）： 项目总结/摘要 疼痛在老年人中非常普遍，但也有很高的可能性没有得到充分的治疗。失败的原因之一是担心目前使用的止痛药的不良副作用。老年人，特别是85岁以上的老年人，在人口中所占的比例越来越大，二战时期退伍军人人口的减少正在被比早期战争中更严重受伤的退伍军人所取代。因此，迫切需要开发具有更少副作用的新疼痛治疗方法，包括那些对老年人特别有问题的疼痛治疗方法。作用于mu（吗啡）受体的阿片类药物代表了绝大多数临床使用的阿片类药物，并且在治疗中度至重度疼痛方面仍然是最有效的。然而，吗啡和类似化合物用于疼痛管理的使用受到不良副作用的限制，所述不良副作用包括呼吸抑制、滥用可能性以及运动和认知障碍。此外，最近的研究表明，重复注射吗啡，甚至几天，可以诱导神经胶质激活，这是一种炎症反应，可以导致“矛盾的”吗啡引起的疼痛。这在治疗已经易受炎症诱导的病理的患者（包括老年人）的疼痛中可能特别重要。该计划的目标是开发新的μ阿片受体激动剂，提供有效的镇痛（抗伤害），相对于吗啡的不良副作用较少。待测试的化合物是基于我们实验室中发现的内源性阿片样物质（内吗啡）的结构的类似物，其已被证明比吗啡产生更少的呼吸抑制和奖励（滥用潜力）。许多老年人的呼吸功能受损，阿片类药物引起的呼吸抑制可能会加剧。运动协调障碍在更容易发生福尔斯和骨折并造成严重后果的患者中可能特别严重。阿片类药物也会损害认知功能。老年人，特别是那些有轻度认知障碍，退行性疾病或创伤性脑损伤的人，可能特别容易受到阿片类药物副作用的影响。一个主要的假设是，这些类似物将产生更少的神经运动和认知障碍，在年轻，中年和老年大鼠比吗啡。该假设将在运动协调的旋转杆测试、空间记忆的Morris Water迷宫测试和对象记忆的对象识别任务中进行测试。对这些任务产生已知损害的吗啡剂量将与内吗啡肽类似物的等镇痛剂量相匹配，以提供相对镇痛/副作用比的有效比较。将测试急性和慢性治疗的效果。另一个假设是，在用吗啡而不是类似物长期治疗后，将在关键脑区观察到胶质细胞活化和神经发生受损。在许多研究中，过度的神经胶质活化和受损的神经发生与认知障碍有关，预计这些神经化学变化将与本项目中测量的行为变化相关。如果成功，该计划将提供新的化合物，用于更有效的疼痛管理，副作用比目前的药物更少，对老年人特别有价值。