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

慢性疼痛影响着数百万美国人，每年花费超过6350亿美元。慢性疼痛的负担 严重倾向于老年人。例如，在25-44岁的成年人中，慢性疼痛的患病率为13.2% 老年人，但人口中33.6%的人已经85岁了。老年人的疼痛不仅对生活质量产生负面影响， 增加虚弱，还与抑郁和认知能力下降有关。因此，研究老年人的慢性疼痛 个人，特别是疼痛的发病机制，疼痛慢性化背后的机制，以及共病 疼痛和其他与衰老相关的问题之间的相互作用是迫切需要的。然而，年龄基本上是 在临床前疼痛研究中被忽略为生物学变量。在初步研究中，我们检查了老年人的疼痛 与幼年动物相比，动物具有独特的特征。具体地说，我们用CFA挑战动物 诱导关节炎，并在2个月(幼年)、12个月(成年)和25个月大时检查伤害性行为 (老龄)C57BL/6小鼠。结果表明，在踝关节同样的炎性侮辱导致显著的 各年龄组均有机械性痛觉异常。然而，机械性超敏持续了大约4周， 幼龄、成年和老龄小鼠分别为4周和7周。这些动物的热痛觉过敏 分别持续约3周、3.5周和6周。我们排除了未解决的关节炎症 反应是老年小鼠伤害性反应延长的原因。因此，年老的动物很可能 表现出与衰老相关的疼痛时代化。我们的实验室此前发现，pGC-1是一种主调节因子 线粒体的生物发生与疼痛的时序化有关。更有趣的是，初步数据还表明 与年轻小鼠相比，老年小鼠在躯体感觉皮质中表达的pGC-1水平较低。 PGC-1主要在中间神经元中表达，对中间神经元的功能起关键作用，其功能障碍已被 与衰老中的功能和认知衰退有关。因此，我们假设衰老与 躯体感觉皮层前列腺素C-1水平降低，损害神经元间功能，促进疼痛 编年史。我们计划实施两个具体目标来检验这一假说。目标1：检查以下项目的影响 年龄对疼痛中神经元活动的影响。目的2：研究衰老过程中疼痛的时代化是否可以通过增加 躯体感觉皮层PGC-1表达水平。综上所述，R03 GEMMSTAR提案旨在研究 在临床前模型中，年龄作为疼痛的生物学变量，特别是与衰老相关的疼痛时代化。 这是一个具有重大临床意义的领域，但到目前为止还没有得到多少研究关注。这笔赠款是 创新之处在于它结合了分子生物学、尖端的活体双光子显微镜和行为学 检测前列腺素C-1和中间神经元在衰老和疼痛时代化中的关键作用。成功执行 这笔赠款将为与衰老相关的疼痛编年化提供新的机械见解，以告知未来 翻译和临床研究。

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.