Aging Promotes Pain Chronification through Changes in PGC-1alpha Expression and Interneuron Dysfunction

衰老通过 PGC-1α 表达的变化和中间神经元功能障碍促进疼痛慢性化

• 批准号: 10026358
• 负责人: Shiqian Shen
• 金额: $ 16.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10026358
• 关键词: Adjuvant; Adult; Affect; Age; Aging; American; Animals; Applications Grants; Area; Arthritis; Attention; Behavior; Behavioral Assay; Biogenesis; Biological; C57BL/6 Mouse; Calcium; Centers for Disease Control and Prevention (U.S.); Clinical Research; Data; Diabetes Mellitus; Elderly; Emotional; Exhibits; Functional disorder; Future; Grant; Heart Diseases; Impaired cognition; Impairment; Individual; Inflammatory; Inflammatory Arthritis; Inflammatory Response; Interneuron function; Interneurons; Joints; Malignant Neoplasms; Mediating; Mental Depression; Mitochondria; Molecular; Molecular Biology; Mood Disorders; Morbidity - disease rate; Mus; Neurons; Nociception; Outcome; Pain; Pain Research; Pathogenesis; Population; Pre-Clinical Model; Prevalence; PubMed; Quality of life; Rattus; Reporting; Research; Role; Somatosensory Cortex; Testing; Thermal Hyperalgesias; age group; aged; ankle joint; arthritic pain; calmodulin-dependent protein kinase II; chronic pain; clinically significant; comorbidity; cost; frailty; functional decline; human very old age (85+); inflammatory pain; innovation; insight; juvenile animal; mechanical allodynia; mortality; mouse model; nociceptive response; novel; pre-clinical; sensor; somatosensory; stem; therapeutic target; translational study; two photon microscopy; young adult

Chronic pain affects millions of Americans and costs more than $635 billion yearly. The burden of chronic pain is heavily tilted toward older adults. For example, the prevalence of chronic pain is 13.2% in adults 25-44 years old, but 33.6% in population >85 years old. Pain in older adults not only negatively impacts quality of life, increases frailty, but also is related with depression and cognitive decline. As such, studying chronic pain in older individuals, particularly the pathogenesis of pain, the mechanisms behind pain chronification, and the comorbid interactions between pain and other aging related issues is urgently warranted. Age, however, has largely been ignored as a biological variable in preclinical pain research. In preliminary studies, we examined if pain in older animals has unique features than that in younger animals. Specifically, we challenged animals with CFA to induce arthritis, and examined nociceptive behavior in 2 months (young), 12 months (adult), and 25 months old (aged) C57BL/6 mice. Results indicate that the same inflammatory insult in ankle joint led to significant mechanical allodynia in all age groups. However, the duration of mechanical allodynia lasted for about 4 weeks, 4 weeks, and 7 weeks, in young, adult, and aged mice respectively. Thermal hyperalgesia in these animals lasted about 3 weeks, 3.5 weeks, and 6 weeks, respectively. We ruled out unresolved joint inflammatory responses as the cause of prolonged nociceptive responses in aged mice. It is therefore likely that aged animals exhibited pain chronification associated with aging. Our lab has previously found that PGC-1, a master regulator of mitochondria biogenesis, is implicated in pain chronification. More intriguingly, preliminary data also indicate that aged mice expressed lower levels of PGC-1 in somatosensory cortex than their younger counterparts. PGC-1 is preferentially expressed in, and critical for the function of, interneurons, whose dysfunction has been associated with functional and cognitive decline in aging. As such, we hypothesize that aging is associated with decreased somatosensory cortex PGC-1 levels, which impairs interneuron function and facilitates pain chronification. We plan to carry out two Specific Aims to test this hypothesis. Aim 1: To examine the impact of age on neuronal activities in pain. Aim 2: To study if pain chronification in aging can be ameliorated by increasing PGC-1 levels in somatosensory cortex S1. Taken together, this R03 GEMMSTAR proposal aims at examining age as a biological variable in pain, particularly in pain chronification associated with aging, in a preclinical model. This is an area that has great clinical significance but has received little research attention to date. This grant is innovative as it combines molecular biology, cutting edge intravital two-photon microscopy, and behavioral assays to examine a key role for PGC-1 and interneuron in aging and pain chronification. Successful execution of this grant will provide novel mechanistic insights into pain chronification associated with aging, to inform future translational and clinical studies.

慢性疼痛会影响数百万美国人，每年成本超过6350亿美元。慢性疼痛的灼伤 大量倾斜到老年人。例如，慢性疼痛的患病率为13.2％，成人25 - 44年 年龄较大，但人口> 85岁。老年人的疼痛不仅会对生活质量产生负面影响 增加脆弱，但也与抑郁症和认知能力下降有关。因此，研究老年人的慢性疼痛 个体，尤其是疼痛的发病机理，疼痛回19的机制和合并症 迫切需要疼痛与其他与衰老有关的问题之间的相互作用。但是，年龄在很大程度上已经 在临床前疼痛研究中被忽略为生物变量。在初步研究中，我们检查了年龄较大的疼痛是否 动物具有独特的特征，而在年轻动物中具有独特的特征。具体来说，我们向CFA的动物挑战 诱导关节炎，并检查了2个月（年轻），12个月（成人）和25个月大的伤害性行为 （老年）C57BL/6小鼠。结果表明，踝关节中相同的炎症损伤导致显着 所有年龄段的机械异常性症。但是，机械性异常性疾病的持续时间持续了大约4周， 年轻，成人和老年小鼠分别为4周和7周。这些动物的热痛觉过敏 分别持续了大约3周，3.5周和6周。我们排除了未解决的关节炎症 反应是老年小鼠的长时间伤害性反应的原因。因此，老年动物很可能 表现出与衰老相关的疼痛回归。我们的实验室以前已经发现，主调节器PGC-1 线粒体生物发生，暗示在疼痛编年期中。更有趣的是，初步数据也表明 老年小鼠在体感皮层中的PGC-1水平低于年轻的小鼠。 PGC-1优选在中间神经元的功能中表达，并且其功能障碍一直是 与衰老的功能和认知能力下降有关。因此，我们假设衰老与 降低体感皮层PGC-1水平，会损害中间神经元的功能并促进疼痛 计算。我们计划执行两个特定的目的来检验这一假设。目标1：检查 目标2：研究是否可以通过增加来改善衰老中的疼痛状态 体感皮质S1中的PGC-1水平。综上所述，此R03 Gemmstar提案旨在检查 临床前模型中的年龄是疼痛的生物学变量，尤其是在与衰老相关的疼痛变化中。 这个领域具有很大的临床意义，但迄今为止很少受到研究的关注。这笔赠款是 创新，因为它结合了分子生物学，尖端插入式两光子显微镜和行为 检验PGC-1和中间神经元在衰老和疼痛编年期中的关键作用的测定。成功执行 这笔赠款将提供有关与衰老相关的疼痛变化的新型机械见解，以告知未来 翻译和临床研究。