Neonatal Pain, Depression and Pain Susceptibility at Maturity in Rats

描述(由申请人提供)：慢性疼痛在美国正接近流行比例，最近报告的患病率在以人口为基础的大样本中占三分之一。疼痛和抑郁紧密地交织在一起，各自预示着对方的严重程度。早产及其伴随的反复疼痛暴露，都会改变躯体感觉过程，并增加成年后患抑郁症的风险。我们建议在雌性和雄性大鼠身上进行生命过程建模研究，以因果关系地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条件的影响，即早期生活疼痛和抑郁。反复的早期新生儿疼痛体验模拟了一个非常年轻或早产的新生儿在新生儿重症监护病房可能经历的痛苦程序。在成熟后，动物保持不受干扰或接受消极情绪诱导，利用长期和重复的社会失败范例，暴露在占主导地位的居民面前。最后，动物接受后爪福尔马林注射，这是一种紧张性疼痛模型，用于评估注射后60分钟内的急性伤害性行为，并在随后的几周内测量炎症诱导的温度和机械过敏。具体目的是确定：(1)反复的早期新生儿疼痛经历和社会挫败是否会增加福尔马林注射后的急性伤害性行为；(2)反复的早期新生儿疼痛经历和社会挫败是否会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久性；(3)社会挫败是否改变基线(福尔马林注射前)热敏感度或机械敏感度；(4)持续性炎症诱导的超敏反应对抑郁生物行为指标的影响；以及(5)三环抗抑郁剂丙咪嗪的治疗是否改善社会挫败感导致的急性伤害性行为严重程度的增加。一项跨越寿命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，以及由此导致的炎症诱导的痛敏状态的严重性和持久性，因素包括：雌性与雄性；出生后第1-8天的戳与触摸；慢性社会失败与家庭笼子控制；以及后爪福尔马林与生理盐水。第二个实验设计针对在正常条件下饲养的成年大鼠的目标5，考虑了性别、社会挫败感和丙咪嗪与载体的因素，以对后爪福尔马林注射的急性伤害性行为反应为关键结果指标。除了传统的使用一般线性混合模型的完全析因设计分析策略外，我们计划采用并行的部分析因设计，这有可能支持在复杂研究中使用更少的动物，尤其是在涉及疼痛和压力的研究中。这项拟议工作的意义涉及到对早期生活痛苦和抑郁对持续性疼痛发展的相对贡献进行因果评估的能力，以及本生命过程研究中采用的模型的病因学有效性。 与公共健康相关：近三分之一的美国人报告患有慢性疼痛，六分之一的人一生中患有严重的抑郁障碍；疼痛和抑郁紧密交织在一起，各自预示着对方的严重程度。早产及其伴随的反复疼痛暴露，都会改变疼痛处理过程，并增加成年后患抑郁症的风险。这项拟议的研究与人类健康的相关性是使用寿命方法来测试早期生活疼痛和成熟时的抑郁是否会增加发生持续性疼痛的风险。

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.