Novel Analgesics for Improved Pain Therapy in Advancing Age

描述(由申请人提供)： 项目摘要/摘要疼痛在老年人中非常普遍，但也很有可能得不到适当的治疗。失败的原因之一是对目前使用的止痛药的不良副作用的担忧。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，而二战时期退伍军人人数的下降正被比以前战争中更严重的伤势存活的退伍军人所取代。因此，迫切需要开发副作用更少的新的疼痛治疗方法，包括那些对老年人特别有问题的治疗方法。作用于MU(吗啡)受体的阿片类药物占临床使用的阿片类药物的绝大多数，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止痛受到不良副作用的限制，包括呼吸抑制、滥用潜力以及运动和认知障碍。此外，最近的研究表明，重复注射吗啡，即使只有几天，也会诱导神经胶质细胞的激活，这是一种炎症反应，可能会导致吗啡诱导的疼痛。这在治疗已经容易受到炎症诱导的病理影响的患者(包括老年人)的疼痛方面可能特别重要。该计划的目标是开发新型的Mu阿片激动剂，提供有效的止痛(抗伤害)，与吗啡相比副作用较少。被测试的化合物是基于我们实验室发现的内源性阿片类药物(内吗啡)的结构的类似物，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会加剧这种情况。运动协调能力的损害在那些更有可能发生跌倒和骨折并造成严重后果的患者中尤其严重。阿片类药物也被认为会损害认知功能。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，与吗啡相比，这些类似物在年轻、中年和老年大鼠身上产生的神经运动和认知障碍更少。这一假设将在运动协调的ROTRORD测试、空间记忆的莫里斯水迷宫测试和对象记忆的对象识别任务中得到验证。在这些任务中产生已知损害的吗啡剂量将与等量的内吗啡类似物的伤害感受剂量相匹配，以提供相对镇痛/副作用比率的有效比较。将测试急性和慢性治疗的效果。另一个假设是，在长期使用吗啡治疗后，可以在关键的大脑区域观察到神经胶质细胞的激活和神经发生的障碍，但不是类似物。在许多研究中，过度的神经胶质细胞激活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，以更有效的疼痛控制，比目前的药物副作用更少，对老年人具有特别的价值。

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.