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，强有力的证据表明，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)的下降， 内源性疼痛抑制的心理物理指标。然而，年龄背后的核心机制 CPM的差异以及CPM功能障碍与慢性疼痛之间的因果联系在很大程度上是 未知。该项目探索了下行有害抑制的年龄差异背后的大脑网络。 控制(DNIC)，一种在临床前环境中类似于CPM的措施，以及 功能障碍的DNIC和骨关节炎(OA)相关的疼痛，这是一种慢性疼痛状况，对 老年人口。我们先前的工作表明，DNIC的效率在年轻女性中降低 在老年大鼠中，DNIC的效率也受到损害。此外，我们还演示了与办公自动化相关的 原发性机械痛敏在老年大鼠中持续时间更长，在老年雌性大鼠中更明显 经历了最严重的衰老影响。然后我们提供了令人信服的证据，证明 年轻雌性大鼠和老年大鼠之间的静息功能连接性(FC)较弱 嘴前扣带回皮质(RACC)和中脑导水管周围灰质(PAG)。我们的研究共同表明 PAG Fc的强rACC是有效DNIC的基石，并且rACC向PAG Fc的年龄相关改变 导致DNIC功能障碍和慢性骨性关节炎疼痛。在这里，我们提出了对rACC到PAG电路增强 老年大鼠DNIC改善，老年大鼠加强DNIC可有效缓解慢性 骨性关节炎疼痛反应。我们将以三个具体目标(SA)来调查我们的提案。我们假设 选择性激活投射到PAG的rACC神经元将显著提高老年大鼠的DNIC效率。 我们将使用DNIC的行为范式与化学遗传学相结合来实验性地操纵强度 老年雄性和雌性大鼠rACC至PAG环路的变化。(SA2)我们将调查潜在的原因 DNIC与老年大鼠骨性关节炎反应的关系我们假设通过以下方式提高DNIC效率 增强rACC到PAG的回路显著改善老年大鼠的骨性关节炎预后。我们将进行一项 同时进行的fMRI研究证实，对DNIC电路的实验性操作可以恢复OA诱导的改变 在老年雄性和雌性大鼠的大脑网络中。(SA3)众所周知，锻炼可以提高人类的CPM。我们的 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 这项运动增加了rACC到PAG电路的强度，从而增强了DNIC，减少了与OA相关的 疼痛，以及恢复老年雄性和雌性大鼠改变的大脑网络。这些研究将显著改善 我们关于衰老对疼痛处理的影响的知识，这是疼痛研究的一个领域，在很大程度上 不够充分。我们的动物模型允许对年龄相关变化背后的大脑回路进行严格的验证 在DNIC中，以及在老年人群中DNIC功能障碍与慢性骨性关节炎疼痛之间的机制联系。 翻译过来，这些结果有望对药理学和非药理学产生新的见解。 加强CPM的策略，加深我们对骨性关节炎疼痛和疼痛的可行循证治疗的理解 可能对老年人的其他慢性疼痛状况有影响。

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.