Aging, peripheral pain and analgesia

描述（由申请人提供）：疼痛的管理是一个重要的问题，在老年人群。65岁以上人群的疼痛发生率可高达80%，许多人报告称持续疼痛限制了日常活动，影响了生活质量。此外，老年人对药物的不良反应更敏感，并且经常服用多种药物，这增加了药物不良相互作用的可能性，特别是在中枢神经系统内。因此，老年人迫切需要更有效的镇痛治疗，随着老年人口（65岁以上）预计到2050年将翻一番，这将变得更加关键。老年人不仅有更多的引起疼痛的疾病和状况，他们的伤害（痛觉）感觉系统也可能对有害刺激更敏感。外周感觉神经元（即痛觉神经元也称为“伤害感受器”）对有害刺激作出反应，并将信号传递给中枢神经系统，将其解释为疼痛。这些神经元参与多种疼痛状况，包括急性损伤、急性炎症性疾病和最常见的神经性疼痛（外周）。然而，关于衰老对外周痛觉神经元影响的研究却很少。我们的初步数据显示，与年轻大鼠（4个月）相比，老年大鼠（26个月）对某些伤害感受器刺激物（如炎症介质）的诱导疼痛更为敏感。这一发现表明，老年大鼠的痛觉感受器更敏感，这表明抑制痛觉感受器的药物可能是有效的镇痛药。阿片受体由伤害感受器表达，当被激活时抑制伤害感受器疼痛信号。不进入中枢神经系统的外周限制性阿片类药物对于没有严重中枢神经系统介导的不良反应（如呼吸抑制、成瘾、烦躁不安）的老年人来说是一种强效镇痛药。然而，年龄对外周阿片受体功能和调节的影响尚不清楚。这项工作的一个主要目标是通过一系列综合的大鼠体内行为分析和培养大鼠伤害感受器的离体实验来描述年龄对伤害感受器功能和调节的影响。此外，我们建议研究年龄对伤害感受器中阿片受体系统的影响。我们的具体目的是：1)确定年龄对外周伤害感受器反应性的影响；2)描述年龄对外周伤害感受器表达的阿片受体功能的影响。我们假设1)痛觉感受器的反应性随着年龄的增长而增加，2)外周限制性阿片激动剂的镇痛效力和/或疗效随着年龄的增长而增加。本研究结果将为研究衰老对外周痛觉神经元（痛觉感受器）功能和调控的影响提供基础信息。这些数据对于提出机制假设（例如蛋白质表达、受体亲和力等的变化）是必要的，这些机制是伤害感受器功能和外周阿片受体系统反应性的年龄相关变化的基础，并可能导致新的外周限制性、更安全的老年人群镇痛药。

DESCRIPTION (provided by applicant): Management of pain is a significant problem in the geriatric population. The incidence of pain for those over the age of 65 can reach as high as 80%, with many reporting persistent pain that limits daily activity and interferes with quality of life. Moreover, the elderly are more sensitive to adverse effects of drugs and are often taking multiple medications that increase the likelihood of adverse drug interactions, especially those within the CNS. Thus, there is a substantial need for more effective analgesic treatments in older adults, which will only become more critical as the geriatric population (aged over 65) is expected to double by 2050. Not only do the elderly have more pain-causing diseases and conditions, their nociceptive (pain-sensing) sensory system may also be more sensitive to noxious stimuli. Peripheral sensory neurons (i.e., pain-sensing neurons also called "nociceptors") respond to noxious stimuli and transmit signals to the CNS that are interpreted as pain. These neurons participate in a variety of pain conditions, including acute injury, acute inflammatory disorders and the most prevalent form of neuropathic pain (peripheral). However, there are very few studies on the effect of aging on peripheral pain-sensing neurons. Our preliminary data show that compared to young rats (4 month), aged rats (26 month) are considerably more sensitive to induction of pain in response to certain nociceptor stimulators (e.g. inflammatory mediators). This finding, that nociceptors are more sensitive in aged rats, suggests that drugs that inhibit nociceptors would be effective analgesics. Opioid receptors are expressed by nociceptors and when activated inhibit nociceptor pain signaling. Peripherally-restricted opioid drugs that do not enter the CNS would be powerful analgesics for the elderly that are devoid of severe CNS- mediated adverse effects (e.g. respiratory depression, addiction, dysphoria). However, nothing is known of the effects of age on the function and regulation of peripheral opioid receptors. A major goal of this work is to delineate the effects of age on nociceptor function and regulation using an integrated series of in vivo rat behavioral assays and ex vivo experiments with rat nociceptors in culture. Further, we propose to investigate the effects of age on opioid receptor systems in nociceptors. Our specific aims are: 1) To determine the effect of age on the responsiveness of peripheral nociceptors, and 2) To delineate the effect of age on function of peripheral opioid receptors expressed by nociceptors. We hypothesize that 1) the responsiveness of nociceptors increases with age, and 2) peripherally-restricted opioid agonists have increased analgesic potency and/or efficacy with age. Results from this work will provide fundamental information about the effects of aging on function and regulation of peripheral pain-sensing neurons (nociceptors). These data are necessary to develop hypotheses of mechanisms (e.g. changes in protein expression, receptor affinity, etc.) that underlie age-related changes in nociceptor function and peripheral opioid receptor system responsiveness and that may lead to new peripherally-restricted, safer analgesics for the geriatric population.