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

与年龄相关的内源性疼痛调节能力下降及其对骨关节炎疼痛的影响

• 批准号: 10627950
• 负责人: JIN Y Ro
• 金额: $ 50.96万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10627950
• 关键词: Absence of pain sensation; Adult; Affect; Age; Aging; Animal Model; Anterior; Area; Attenuated; Back; Behavioral Paradigm; Brain; Chronic; Data; Degenerative polyarthritis; Development; Elderly; Elderly woman; Evidence based treatment; Exercise; Female; Functional Magnetic Resonance Imaging; Functional disorder; Genetic; Human; Hyperalgesia; Impairment; Knowledge; Link; Measures; Mechanics; Mediating; Meta-Analysis; Microinjections; Morphine; Naloxone; National Health Interview Survey; Neurons; Outcome; Pain; Pain Disorder; Pain Research; Pain management; Persistent pain; Persons; Pharmacological Treatment; Phase; Population; Pre-Clinical Model; Prevalence; Primary Hyperalgesias; Psychophysics; Rattus; Reporting; Rest; Risk; Role; System; Validation; Woman; Work; age difference; age effect; age related; aged; aging population; brain circuitry; chronic pain; chronic pain management; chronic painful condition; cingulate cortex; clinical pain; clinical translation; conditioned pain modulation; diffuse noxious inhibitory control; evidence base; experience; imaging study; improved; indexing; insight; male; midbrain central gray substance; neural; novel; optimal treatments; osteoarthritis pain; pain inhibition; pain outcome; pain processing; pharmacologic; pre-clinical; response; scale up; sex; tool; treatment strategy

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.

摘要和项目总结 越来越多的研究表明，有一种机制使老年人容易患上抑郁症 慢性疼痛风险增加是由于年龄相关的条件性疼痛调节（CPM）下降， 内源性疼痛抑制的心理物理指数。然而，年龄背后的核心机制 CPM 的差异以及功能失调的 CPM 与慢性疼痛之间的因果关系在很大程度上是 未知。该项目探讨了导致有害抑制下降的年龄差异背后的大脑网络 控制（DNIC），一种类似于临床前设置中的 CPM 的措施，以及之间的机械联系 功能失调的 DNIC 和骨关节炎 (OA) 相关疼痛，一种慢性疼痛状况，对患者的影响尤为严重 老年人口。我们之前的工作表明，年轻女性的 DNIC 效率会降低 大鼠中，DNIC 效率在雌雄老年大鼠中也受到损害。此外，我们还证明了 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且更明显，其中老年雌性大鼠 经历最严重的衰老影响。然后我们提供了令人信服的证据证明 DNIC 的改变 年轻雌性大鼠和老年大鼠之间的静息功能连接（FC）较弱密切相关 头侧前扣带皮层 (rACC) 和导水管周围灰质 (PAG)。我们的研究共同表明 强大的 rACC 到 PAG FC 是高效 DNIC 的基石，并且 rACC 到 PAG FC 的年龄相关变化 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 电路 老年大鼠的 DNIC 会得到改善，并且加强老年大鼠的 DNIC 将有效减轻慢性 OA 疼痛反应。我们将根据三个具体目标 (SA) 来研究我们的提案。 (SA1) 我们假设 选择性激活投射到 PAG 的 rACC 神经元将显着提高老年大鼠的 DNIC 效率。 我们将使用 DNIC 的行为范式与化学遗传学相结合来通过实验操纵强度 老年雄性和雌性大鼠中 rACC 至 PAG 回路的研究。 (SA2) 我们将调查潜在的因果关系 老年大鼠 DNIC 和 OA 反应之间的关系。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。我们将进行一次 并行功能磁共振成像研究证实 DNIC 电路的实验操作可恢复 OA 引起的变化 在老年雄性和雌性大鼠的大脑网络中。 (SA3) 众所周知，运动可以提高人类的 CPM。我们的 初步数据显示，规律运动也能显着改善老年大鼠的DNIC。我们假设 锻炼增加了 rACC 至 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。这些研究将显着改善 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，主要是 不足。我们的动物模型可以对与年龄相关的变化背后的大脑回路进行严格验证 以及老年人群中功能失调的 DNIC 与慢性 OA 疼痛之间的机制联系。 从转化上讲，这些结果有望对药理学和非药理学产生新的见解 增强 CPM 的策略，进一步加深我们对 OA 疼痛的可行循证治疗方法的理解， 可能用于治疗老年人的其他慢性疼痛。