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。认识到老年人慢性疼痛在临床上、生物学上和治疗上都比年轻人疼痛复杂得多，强调了对老年疼痛感知变化的行为改变和生物学机制进行综合研究的必要性。在过去的20年中，与疼痛的外周和中枢底物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到的任何东西都适用于老年人（动物或人类）的疼痛系统。对慢性疼痛发展的细胞和分子机制的研究揭示了与衰老机制不可否认的重叠，从而为评估衰老的生物学过程与慢性疼痛的病理状况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性影响有关的三个具体目标，包括努力确定与年龄有关的热敏性和冷敏性变化的时间特征。热敏性将用一种新的基于操作的行为评估方法进行评估。对8-27月龄雌、雄Fisher Hybrid （f3440）大鼠进行纵向评价，研究年龄对热敏感性的累积效应以及感官变化对身体性能的影响。由于慢性炎症是导致肌肉骨骼疼痛的常见疾病，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。还将评估生命早期慢性损伤对生命后期超敏反应发展的易感性影响。通过检查脊髓小胶质细胞和背根神经节中热受体表达的年龄依赖性变化，将评估感觉功能年龄依赖性变化的潜在中枢与外周机制。提出的研究代表：(a)向与年龄相关的疼痛分子和生理机制的机制研究迈出了重要的一步；(b)将基础疼痛研究转化为与老年人疼痛障碍相关的临床策略的关键环节。为了实现这些目标，一个由疼痛和行为、小胶质细胞、身体表现和统计分析方面的专家组成的多学科团队将被用来执行拟议的研究计划。本研究提出了一种创新的方法，首次将纵向设计与临床相关的操作行为评估策略结合起来，研究年龄对热敏感性的影响。公共卫生相关性：老年人慢性疼痛在临床、生物学和治疗上都比年轻人疼痛复杂得多，因此为研究年龄对慢性疼痛发展和维持的影响提供了理论依据和动机。该研究代表了：(a)对与年龄相关的疼痛行为、分子和生理机制的机制研究迈出了重要的一步；(b)将基础疼痛研究转化为与老年人疼痛障碍相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.