Neonatal Pain, Depression and Pain Susceptibility at Maturity in Rats

大鼠的新生儿疼痛、抑郁和成熟期疼痛敏感性

• 批准号: 7943808
• 负责人: Gayle Giboney Page
• 金额: $ 37.8万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7943808
• 关键词: Acute; Address; Adult; American; Anhedonia; Animals; Behavior; Behavioral; Biological; Body Weight; Centers for Disease Control and Prevention (U.S.); Chronic; Complex; Development; Epidemic; Exhibits; Experimental Designs; Exposure to; Female; Formalin; Health; Healthcare; Home environment; Hour; Human; Hypersensitivity; Imipramine; Individual; Inflammation; Inflammatory; Injection of therapeutic agent; Investigation; Life; Life Cycle Stages; Longevity; Major Depressive Disorder; Measurement; Mechanics; Mental Depression; Modeling; Neonatal; Neonatal Intensive Care Units; Nociception; Organism; Outcome Measure; Pain; Persistent pain; Pre-Clinical Model; Predisposition; Premature Birth; Premature Infant; Prevalence; Procedures; Process; Rattus; Relative (related person); Reporting; Risk; Saline; Sampling; Severities; Sleep; Stress; Study models; Testing; Time; Touch sensation; Tricyclic Antidepressive Agents; United States; Walkers; Work; biobehavior; chronic pain; depressive symptoms; design; experience; indexing; male; negative mood; population based; postnatal; research study; response; sex; social; somatosensory

DESCRIPTION (provided by applicant): Chronic pain is approaching epidemic proportions in the United States with a recently reported prevalence of one-third in a large population based sample. Pain and depression are closely intertwined, each predicting the severity of the other. Preterm birth, and its concomitant repeated pain exposures, both alters somatosensory processes and contributes to risk for depression in adulthood. We propose to employ a life course modeling study in female and male rats to causally evaluate the relative contribution of two factors shown to render individuals susceptible to persistent pain conditions, early life pain and depression. Repeated early neonatal pain experiences model the painful procedures a very young or preterm neonate might undergo in a neonatal intensive care unit. Upon reaching maturity, animals remain unperturbed or undergo negative mood induction utilizing a chronic and repeated social defeat paradigm, exposures to a dominant resident. Finally, animals undergo hind paw formalin injection, a tonic pain model to assess acute nociceptive behavior in the 60 minutes after injection and measurement of inflammation-induced thermal and mechanical hypersensitivity over subsequent weeks. The specific aims are to determine: (1) whether repeated early neonatal pain experiences and social defeat increase acute nociceptive behavior following formalin injection; (2) whether repeated early neonatal pain experiences and social defeat increase the severity and persistence of inflammation-induced hypersensitivity over the weeks subsequent to formalin injection; (3) whether social defeat alters baseline (pre- formalin injection) thermal or mechanical sensitivity; (4) the impact of persistent inflammation-induced hypersensitivity on depressive biobehavioral indices; and (5) whether treatment with the tricyclic antidepressant, imipramine, ameliorates the social defeat induced increase in the severity of acute nociceptive behavior. An experimental design over the lifespan addresses Aims 1 - 4, to determine the effects of repeated early neonatal pain experiences and negative mood at maturity on the acute nociceptive behavioral response to hind paw formalin injection and the severity and persistence of the resulting inflammation-induced hyperalgesic state with factors: female vs male; poke vs touch from postnatal day 1 - 8; chronic social defeat vs home cage control; and hind paw formalin vs saline. A second experimental design addresses Aim 5 in mature rats reared under normal conditions with factors, sex, social defeat, and imipramine vs vehicle, with acute nociceptive behavioral response to hind paw formalin injection as the key outcome measure. In addition to the traditional complete factorial design analysis strategy using general linear mixed models, we plan to employ a fractional factorial design in parallel, which has the potential to support the use of fewer animals in complex studies, particularly important in studies involving pain and stress. The significance of the proposed work relates to the ability to causally evaluate the relative contribution of early life pain and depression to the development of persistent pain, and the etiologic validity of the models employed in this life course study. PUBLIC HEALTH RELEVANCE: Nearly 1 in 3 Americans report chronic pain and 1 in 6 suffer major depressive disorder in their lifetime; and pain and depression are closely intertwined, each predicting the severity of the other. Preterm birth, and its concomitant repeated pain exposures, both alters pain processing and contributes to risk for depression in adulthood. The relevance of the proposed study to human health is the use of a lifespan approach to test whether early life pain and depression at maturity increase risk for the development of persistent pain.

描述（由申请人提供）：在美国，慢性疼痛已接近流行病的比例，最近报告称，在大量人口样本中，慢性疼痛的患病率为三分之一。疼痛和抑郁紧密相连，两者都预示着对方的严重程度。早产及其伴随的反复疼痛都会改变体感过程，并增加成年后患抑郁症的风险。我们建议对雌性和雄性大鼠进行生命历程建模研究，以因果关系评估两个因素的相对贡献，这两个因素使个体容易受到持续性疼痛、早年疼痛和抑郁的影响。重复的早期新生儿疼痛经历模拟了非常年幼或早产新生儿在新生儿重症监护病房可能经历的疼痛过程。成熟后，动物会保持泰然自若，或利用长期且反复的社会挫败范式（暴露于占主导地位的居民）进行负面情绪诱导。最后，动物接受后爪福尔马林注射，这是一种强直性疼痛模型，用于评估注射后 60 分钟内的急性伤害性行为，并测量随后几周内炎症引起的热和机械超敏反应。具体目的是确定：（1）重复的早期新生儿疼痛经历和社交失败是否会增加注射福尔马林后的急性伤害行为； (2) 注射福尔马林后几周内，重复的早期新生儿疼痛经历和社交失败是否会增加炎症引起的超敏反应的严重程度和持续性； (3) 社交失败是否会改变基线（福尔马林注射前）的热或机械敏感性； (4)持续炎症诱发的超敏反应对抑郁生物行为指标的影响； (5)三环类抗抑郁药丙咪嗪治疗是否可以改善社交失败导致的急性伤害性行为严重程度的增加。生命周期的实验设计解决了目标 1 - 4，以确定重复的早期新生儿疼痛经历和成熟时的负面情绪对后爪福尔马林注射的急性伤害性行为反应的影响，以及由此产生的炎症引起的痛觉过敏的严重性和持续性因素状态：女性与男性；产后第 1 - 8 天的戳与触摸；长期的社交失败与家庭笼子控制；和后爪福尔马林与盐水。第二个实验设计针对在正常条件下饲养的成熟大鼠的目标 5，其中包括性别、社交失败和丙咪嗪与媒介物的比较，其中对后爪福尔马林注射的急性伤害行为反应作为关键结果测量。除了使用一般线性混合模型的传统完整析因设计分析策略外，我们计划并行采用部分析因设计，这有可能支持在复杂研究中使用更少的动物，这在涉及疼痛和压力的研究中尤其重要。这项工作的意义在于能够因果评估早期生活疼痛和抑郁对持续性疼痛发展的相对贡献，以及本生命历程研究中采用的模型的病因学有效性。 公共卫生相关性：近三分之一的美国人在一生中患有慢性疼痛，六分之一的人患有严重抑郁症；疼痛和抑郁紧密相连，两者都预示着对方的严重程度。早产以及随之而来的反复疼痛，都会改变疼痛的处理过程，并增加成年后患抑郁症的风险。拟议的研究与人类健康的相关性在于使用寿命方法来测试生命早期的疼痛和成熟时的抑郁是否会增加发生持续性疼痛的风险。