Effects of Age on Thermal Sensitivity

描述(由申请人提供)：年龄增长如何影响负责疼痛体验的生物系统是疼痛研究领域的一个主要挑战。认识到老年人的慢性疼痛在临床、生物学和治疗上比年轻人群的疼痛要复杂得多的事实，强调了综合研究的必要性，包括行为变化和导致疼痛感知随年龄增长而改变的生物学机制。在过去的20年里，与疼痛的外周和中枢基质相关的知识取得了重大进展。不幸的是，几乎没有证据表明我们所学的任何东西都适用于老年人(动物或人类)的疼痛系统。对慢性疼痛发生的细胞和分子机制的研究表明，不可否认的是，与导致衰老的机制存在重叠，从而为研究衰老的生物过程和慢性疼痛的病理状态之间的相互作用提供了理论基础。将讨论与年龄增长对热敏感性的影响有关的三个具体目标，包括努力确定与年龄相关的热敏感性和冷敏感性变化的时间特征。热敏感性将用一种新的基于算子的行为评估方法进行评估。将对动物进行纵向评估，以研究年龄对热敏感性的累积影响，以及感觉变化对8-27个月龄的雄性和雌性Fisher杂交(F344BN)大鼠身体表现的影响。由于慢性炎症是导致肌肉骨骼疼痛的常见疾病，而肌肉骨骼疼痛是老年人残疾的主要原因，因此将努力研究年龄、慢性炎症和炎症损伤后自主神经功能变化之间的相互关系。我们还将评估早期慢性损伤对后期超敏反应发展的易感性影响。将通过检测脊髓小胶质细胞和背根神经节中温度受体表达的年龄相关性变化来评估感觉功能随年龄变化的潜在中枢与外周机制(S)。拟议的研究代表：(A)朝着与年龄相关的疼痛分子和生理机制相关的机制研究迈出了重要的一步；以及(B)将基础疼痛研究转化为与老年人疼痛障碍有关的临床策略的关键环节。为了实现这些目标，将使用一个由疼痛和行为、小胶质细胞、体能表现和统计分析专家组成的多学科团队来执行拟议的研究计划。建议的研究代表了一种创新的方法，首次将纵向设计与临床相关的操作行为评估策略相结合，以研究年龄对热敏感性的影响。与公共卫生相关：老年人的慢性疼痛在临床、生物学和治疗上比年轻人群的疼痛复杂得多，因此为研究年龄对慢性疼痛的发展和维持的影响提供了理论基础和动机。拟议的研究代表：(A)朝着与年龄相关的行为、分子和生理疼痛机制相关的机械学研究迈出了重要的一步；以及(B)将基础疼痛研究转化为与老年人疼痛障碍有关的临床试验策略的关键环节。

DESCRIPTION (provided by applicant): How advancing age impacts biological systems responsible for the experience of pain represents a major challenge in the field of pain research. Acknowledging the fact that chronic pain in the elderly is a far more complex condition clinically, biologically, and therapeutically than pain in younger segments of the population underscores the need for integrative studies encompassing behavioral changes and biological mechanisms responsible for alterations in pain perception with advancing age. Over the past 20 years knowledge related to peripheral and central substrates of pain has seen significant advances. Unfortunately, there is little evidence that anything we have learned applies to the pain system in the elderly (animals or humans). An examination of cellular and molecular mechanisms responsible for the development of chronic pain reveals an undeniable overlap with mechanisms responsible for aging, thus providing the rationale for studies evaluating the interaction between the biological process of aging and the pathological condition of chronic pain. Three specific aims related to the impact of advancing age on thermal sensitivity will be addressed, including efforts to define the temporal characteristics of age-related changes in heat and cold sensitivity. Thermal sensitivity will be evaluated with a novel operant-based method of behavioral assessment. Animals will be evaluated longitudinally to study the cumulative effects of age on thermal sensitivity along with the impact of sensory changes on physical performance in male and female Fisher Hybrid (F344BN) rats ranging in age from 8-27 months. Since chronic inflammation is a common condition contributing to musculoskeletal pain, a primary cause of disability in the elderly, efforts will be made to examine the interrelationships among age, chronic inflammation, and changes in autonomic function following inflammatory injury. The predisposing influence of chronic injury early in life to the development of hypersensitivity later in life will also be evaluated. Potential central versus peripheral mechanism(s) for age-dependent changes in sensory function will be evaluated by examining age-dependent changes in spinal microglia and thermal receptor expression in dorsal root ganglia. The proposed research represents: (a) an essential step towards mechanistic studies related to age- dependent molecular and physiological mechanisms of pain; and (b) a pivotal link for translating basic pain research into clinical strategies related to pain disorders in the elderly. To accomplish these objectives a multidisciplinary team consisting of experts in pain and behavior, microglia, physical performance, and statistical analysis will be used to carry out the proposed Research Plan. The proposed studies represent an innovative approach that for the first time combines a longitudinal design with a clinically relevant strategy of operant behavioral assessment to study the effects of age on thermal sensitivity. PUBLIC HEALTH RELEVANCE: Chronic pain in the elderly is a far more complex condition clinically, biologically, and therapeutically than pain in younger segments of the population thus providing the rationale and motivation for studies directed towards understanding the impact of age on the development and maintenance of chronic pain. The proposed research represents: (a) an essential step towards mechanistic studies related to age-dependent behavioral, molecular and physiological mechanisms of pain; and (b) a pivotal link for translating basic pain research into clinical trial strategies related to pain disorders in the elderly.