Neonatal Pain, Depression and Pain Susceptibility at Maturity in Rats

描述（由申请人提供）：慢性疼痛在美国接近流行病的比例，最近报道的流行率为三分之一，以大量人口为基础的样本。疼痛和抑郁紧密地交织在一起，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，都改变了体感觉过程，并增加了成年后患抑郁症的风险。我们建议在雌性和雄性大鼠中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，这些因素表明个体易受持续疼痛条件的影响，即早期生活疼痛和抑郁。重复的早期新生儿疼痛经历模拟了一个非常年幼或早产的新生儿可能在新生儿重症监护室经历的痛苦过程。在达到成熟期后，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式，暴露于一个占主导地位的居民。最后，动物后爪注射福尔马林，建立强直性疼痛模型，以评估注射后60分钟的急性伤害性行为，并在随后的几周内测量炎症引起的热和机械超敏反应。具体目的是确定：(1)重复的新生儿早期疼痛经历和社会失败是否会增加福尔马林注射后的急性伤害性行为；(2)反复的新生儿早期疼痛经历和社交失败是否会增加福尔马林注射后数周内炎症性超敏反应的严重程度和持久性；(3)社会失败是否改变基线（注射福尔马林前）的热或机械敏感性；(4)持续炎症性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能改善社交失败导致的急性伤害性行为严重程度的增加。一项针对目标1 - 4的终身实验设计，以确定重复的新生儿早期疼痛经历和成熟时的负性情绪对后爪注射福尔马林的急性伤害性行为反应的影响，以及由此产生的炎症性痛觉过敏状态的严重程度和持久性，其因素包括：女性与男性；出生后1 - 8天的Poke vs . touch；长期社会失败vs家庭笼子控制；后爪福尔马林vs生理盐水。第二个实验设计是在正常条件下饲养的成熟大鼠，在性别、社会失败和丙咪嗪与载药的影响下，以后爪注射福尔马林的急性伤害性行为反应为主要结果测量指标。除了使用一般线性混合模型的传统全因子设计分析策略外，我们计划采用平行的分数因子设计，这有可能支持在复杂研究中使用更少的动物，特别是在涉及疼痛和压力的研究中。这项研究的重要意义在于能够评估早期生活疼痛和抑郁对持续性疼痛发展的相对贡献，以及本生命过程研究中采用的模型的病因学有效性。

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.