Aging, peripheral pain and analgesia

衰老、末梢疼痛和镇痛

• 批准号: 8824054
• 负责人: WILLIAM P CLARKE
• 金额: $ 22.61万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824054
• 关键词: Absence of pain sensation; Acute; Adverse drug effect; Adverse effects; Afferent Neurons; Affinity; Age; Age-Months; Aging; Agonist; Analgesics; Behavioral Assay; Bradykinin; Capsaicin; Chemicals; Data; Dinoprostone; Disease; Dose; Drug Interactions; Elderly; Figs - dietary; Goals; Heating; Incidence; Inflammation Mediators; Inflammatory; Injury; Lead; Measures; Mechanical Stimulation; Mechanics; Mediating; Medical; Menthol; Neurons; Nociception; Nociceptors; Nursing Homes; Opioid; Opioid Receptor; Pain; Pain management; Peripheral; Persistent pain; Pharmaceutical Preparations; Play; Population; Quality of life; Rattus; Rattus norvegicus; Regulation; Reporting; Risk; Role; Safety; Series; Signal Transduction; Social Problems; Stimulus; System; Testing; Ventilatory Depression; Withdrawal; Work; addiction; age effect; age group; age related; aged; behavior test; dysphoria; effective therapy; experience; heat stimulus; improved; in vivo; juvenile animal; middle age; mustard oil; neurotransmission; older patient; painful neuropathy; peripheral pain; protein expression; public health relevance; receptor; research study; response; sensory system

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.

描述（由申请人提供）：疼痛管理是老年人群中的一个重要问题。65岁以上人群的疼痛发生率可高达80%，许多人报告持续性疼痛，限制了日常活动并干扰了生活质量。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CNS内的药物。因此，老年人非常需要更有效的镇痛治疗，这只会变得更加关键，因为预计到2050年老年人口（65岁以上）将翻一番。老年人不仅有更多的疼痛引起的疾病和条件，他们的伤害性（疼痛感测）感觉系统也可能对伤害性刺激更敏感。外周感觉神经元（即，疼痛感测神经元（也称为“伤害感受器”）对有害刺激作出反应并将被解释为疼痛的信号传递到CNS。这些神经元参与各种疼痛状况，包括急性损伤、急性炎症性疾病和最普遍形式的神经性疼痛（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（例如炎症介质）引起的疼痛诱导更加敏感。这一发现，即伤害感受器在老年大鼠中更敏感，表明抑制伤害感受器的药物将是有效的镇痛剂。阿片受体由伤害感受器表达，并且当被激活时抑制伤害感受器疼痛信号传导。不进入CNS的外周限制性阿片类药物是老年人的强效镇痛药，没有严重的CNS介导的不良反应（例如呼吸抑制、成瘾、烦躁不安）。然而，年龄对外周阿片受体的功能和调节的影响尚不清楚。这项工作的主要目标是使用一系列综合的体内大鼠行为测定和培养中大鼠伤害性感受器的离体实验来描述年龄对伤害性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。我们的具体目标是：1）确定年龄对外周伤害感受器反应性的影响; 2）描述年龄对伤害感受器表达的外周阿片受体功能的影响。我们假设1）伤害感受器的反应性随着年龄的增长而增加，2）外周限制性阿片类激动剂的镇痛效力和/或功效随着年龄的增长而增加。这项工作的结果将提供有关衰老对外周疼痛感受神经元（伤害感受器）功能和调节的影响的基本信息。这些数据对于发展机制假设（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，并可能为老年人群带来新的外周限制性、更安全的镇痛药。