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: 8434077
• 负责人: Gayle Giboney Page
• 金额: $ 34.88万
• 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/8434077
• 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.

描述（由申请人提供）：慢性疼痛在美国接近流行病的比例，最近报告的流行率为三分之一，在一个大的人口为基础的样本。疼痛和抑郁是紧密交织在一起的，每一个都预示着另一个的严重程度。早产及其伴随的反复疼痛暴露都改变了躯体感觉过程，并导致成年后抑郁的风险。我们建议在雌性和雄性大鼠中采用生命过程建模研究，以因果关系评估两个因素的相对贡献，这两个因素使个体易受持续性疼痛条件，早期生活疼痛和抑郁症的影响。反复早期新生儿疼痛的经验模型的痛苦程序非常年轻或早产儿可能会经历在新生儿重症监护病房。在达到成熟后，动物保持不受干扰或经历负面情绪诱导利用慢性和反复的社会失败范例，暴露于占主导地位的居民。最后，动物经历后爪福尔马林注射，强直性疼痛模型以评估注射后60分钟内的急性伤害感受行为，并测量随后几周内炎症诱导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增加福尔马林注射后的急性伤害性行为;（2）重复的早期新生儿疼痛经历和社交失败是否增加福尔马林注射后数周内炎症诱导的超敏反应的严重性和持续性;（3）社会失败是否改变基线（预福尔马林注射）热或机械敏感性;（4）持续性炎症诱导的超敏反应对抑郁生物行为指数的影响;和（5）用三环类抗抑郁药丙咪嗪治疗是否改善了社交失败诱导的急性伤害性行为严重程度的增加。在寿命期内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，以及所产生的炎症诱导的痛觉过敏状态的严重性和持续性，其中因素为：雌性与雄性;从出生后第1 - 8天戳与触摸;慢性社交失败与家庭笼对照;以及后爪福尔马林与盐水。第二个实验设计解决了在正常条件下饲养的成熟大鼠中的目标5，具有因素、性别、社会失败和丙咪嗪与媒介物，对后爪福尔马林注射的急性伤害性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全析因设计分析策略外，我们计划平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，在涉及疼痛和压力的研究中尤其重要。拟议的工作的意义涉及到因果关系的能力，以评估早期生活的疼痛和抑郁症的发展持续性疼痛的相对贡献，以及在这个生命历程研究中采用的模型的病因学有效性。