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%。 老年人占33.6%，但85岁以上的老年人占33.6%。老年人的疼痛不仅对生活质量产生负面影响， 增加虚弱，但也与抑郁和认知能力下降有关。因此，研究老年人的慢性疼痛 个体，特别是疼痛的发病机制，疼痛慢性化背后的机制，以及共病 疼痛和其他衰老相关问题之间的相互作用是迫切需要的。然而，年龄在很大程度上 在临床前疼痛研究中被忽略的生物学变量。在初步研究中，我们检查了老年人的疼痛是否 动物比年轻的动物具有独特的特征。具体来说，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个月大时检查伤害感受行为 （老年）C57 BL/6小鼠。结果表明，相同的踝关节炎症损伤导致显著的 所有年龄组的机械性异常性疼痛。然而，机械性异常性疼痛持续约4周， 青年、成年和老年小鼠分别为4周和7周。这些动物的热痛觉过敏 分别持续约3周、3.5周和6周。我们排除了未解决的关节炎 反应的原因延长伤害性反应在老年小鼠。因此，老年动物很可能 表现出与衰老相关的疼痛慢性化。我们的实验室以前发现，PGC-1 β，一个主调节器， 线粒体的生物发生，与疼痛的慢性化有关。更有趣的是，初步数据还表明， 老年小鼠在躯体感觉皮层中表达的PGC-1 β水平低于年轻小鼠。 PGC-1 β优先在中间神经元中表达，并且对中间神经元的功能至关重要， 与衰老中的功能和认知能力下降有关。因此，我们假设衰老与 躯体感觉皮层PGC-1 β水平降低，损害中间神经元功能并促进疼痛 时间顺序我们计划进行两个特定目标来验证这一假设。目标1：审查 年龄对疼痛中神经元活动的影响目的2：研究是否可以通过增加 躯体感觉皮层S1中的PGC-1水平。综上所述，R 03 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，特别是在与衰老相关的疼痛慢性化中。 这是一个具有重要临床意义的领域，但迄今为止很少受到研究关注。这笔赠款是 创新，因为它结合了分子生物学，尖端的活体双光子显微镜， 本发明涉及一种检测PGC-1 β和中间神经元在衰老和疼痛慢性化中的关键作用的测定。成功执行 这项拨款将提供新的机制的见解疼痛慢性化与衰老相关，以告知未来 转化和临床研究。

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.