Age-related decline in endogenous pain modulation and its impact on osteoarthritis pain

摘要和项目摘要 越来越多的研究表明，有一种机制使老年人容易患上 慢性疼痛状况的风险增加是与年龄相关的条件性疼痛调制（CPM）下降， 内源性疼痛抑制的心理物理指标。然而，年龄的核心机制 CPM的差异以及功能失调的CPM和慢性疼痛状况之间的因果关系在很大程度上是 未知这个项目探讨了大脑网络的基础年龄差异下降有害抑制 对照（DNIC），一种类似于临床前环境中CPM的测量方法，以及 功能失调的DNIC和骨关节炎（OA）相关疼痛，一种慢性疼痛状况，不成比例地影响 老年人口。我们之前的工作已经证明，年轻女性的DNIC效率会降低 大鼠，并且DNIC效率在两种性别的老年大鼠中也受损。此外，我们还证明了与OA相关的 原发性机械性痛觉过敏在老年大鼠中持续时间更长，更明显，老年雌性大鼠 经历着最严重的衰老效应然后，我们提供了令人信服的证据，证明在 年轻雌性大鼠和老年大鼠之间的静息功能连接（FC）较弱 前扣带皮层（rACC）和中脑导水管周围灰质（PAG）。我们的研究表明 强rACC至PAG FC是有效DNIC的基石，rACC至PAG FC的年龄相关改变 导致DNIC功能失调和慢性OA疼痛。在这里，我们建议增强rACC到PAG回路， 在老年大鼠中，增强DNIC将有效地减轻慢性炎症， OA疼痛反应。我们将研究我们的建议与三个具体目标（SA）。(SA1)我们假设 选择性激活投射到PAG的rACC神经元将显著增强老年大鼠的DNIC效率。 我们将使用DNIC与化学遗传学配对的行为范例来实验性地操纵强度。 老年大鼠rACC-PAG回路的变化。(SA2)我们将调查潜在的因果关系 老年大鼠DNIC与OA反应的关系我们假设，通过以下方式提高DNIC效率 增强rACC至PAG回路可显着改善老年大鼠的OA结局。我们将进行 同时进行的fMRI研究，以证实DNIC回路的实验操作恢复了OA诱导的变化 老年雄性和雌性大鼠的大脑网络中。(SA3)众所周知，运动可以增强人类的CPM。我们 初步数据显示，规律运动也能显著改善老年大鼠的DNIC。我们假设 运动增加了rACC到PAG回路的强度，从而增强了DNIC，减少了OA相关的 疼痛，并恢复老年雄性和雌性大鼠改变的大脑网络。这些研究将大大改善 我们关于衰老对疼痛处理的影响的知识，疼痛研究的一个领域， 不足我们的动物模型允许严格验证与年龄相关变化的大脑回路 以及老年人群中功能失调的DNIC和慢性OA疼痛之间的机制联系。 这些结果有望在药理学和非药理学方面产生新的见解。 加强CPM的策略，进一步了解OA疼痛的可行循证治疗， 可能用于老年人的其他慢性疼痛状况。

Abstract and Project Summary A growing number of studies show strong evidence that one mechanism predisposing older adults to an increased risk of chronic pain conditions is an age-related decline in conditioned pain modulation (CPM), a psychophysical index of endogenous pain inhibition. However, the central mechanisms underlying age differences in CPM and the causal links between dysfunctional CPM and chronic pain conditions are largely unknown. This project explores the brain networks that underlie age differences in descending noxious inhibitory control (DNIC), a measure that is similar to CPM in preclinical settings, and the mechanistic links between dysfunctional DNIC and osteoarthritis (OA)-related pain, a chronic pain condition that disproportionately affects the aged population. Our prior work has demonstrated that the efficiency of DNIC is reduced in young female rats, and DNIC efficiency is also impaired in old rats of both sexes. Additionally, we demonstrated that OA-related primary mechanical hyperalgesia was longer-lasting and more pronounced in older rats, with aged female rats experiencing the most severe aging effects. We then provided compelling evidence that the altered DNIC in young female rats and old rats is strongly associated with a weaker resting functional connectivity (FC) between the rostral anterior cingulate cortex (rACC) and the periaqueductal gray (PAG). Our studies collectively suggest that strong rACC to PAG FC is a cornerstone of efficient DNIC, and age-related alteration in rACC to PAG FC leads to dysfunctional DNIC and chronic OA pain. Here we propose that enhancement of the rACC to PAG circuit in aged rats will lead to improved DNIC and that strengthening DNIC in aged rats will effectively attenuate chronic OA pain responses. We will investigate our proposal with three specific aims (SAs). (SA1) We hypothesize that selective activation of rACC neurons projecting to PAG will significantly enhance DNIC efficiency in aged rats. We will use a behavioral paradigm for DNIC paired with chemogenetics to experimentally manipulate the strength of the rACC to PAG circuit in aged male and female rats. (SA2) We will investigate the potential causal relationship between DNIC and OA responses in aged rats. We hypothesize that scaling up DNIC efficiency by enhancing the rACC to PAG circuit significantly improves OA outcomes in aged rats. We will conduct a concurrent fMRI study to confirm that experimental manipulation of DNIC circuitry restores OA-induced changes in the brain networks of aged male and female rats. (SA3) Exercise is known to enhance CPM in humans. Our preliminary data show that regular exercise can also significantly improve DNIC in aged rats. We hypothesize that exercise increases the strength of the rACC to PAG circuit, thereby enhancing DNIC, reducing OA-related pain, and restoring altered brain networks in aged male and female rats. These studies will significantly improve our knowledge regarding the impact of aging on pain processing, an area of pain research that has been largely inadequate. Our animal models allow rigorous validation of the brain circuits that underlie age-related changes in DNIC and of the mechanistic links between dysfunctional DNIC and chronic OA pain in the aged population. Translationally, these results promise to yield novel insights into both pharmacological and non-pharmacological strategies to enhance CPM, furthering our understanding of viable evidence-based treatments for OA pain and potentially for other chronic pain conditions in the elderly.