Neonatal Pain, Adult Biobehavioral Responses to Stress

描述（由申请人提供）：早产儿和危重新生儿是最脆弱的人群之一，需要重症护理，其特点是多个程序，其中许多是痛苦的。最近在早产儿和新生大鼠中的研究提供了证据，表明神经系统在无与伦比的神经感觉可塑性期间对疼痛刺激更敏感。鉴于新生大鼠的重复性非疼痛事件已被证明会影响成熟动物对应激的神经内分泌和免疫反应，因此重复的疼痛应激源可能会对成熟动物产生更深远的影响。资助研究的总体目标是在成熟动物中探索重复性新生儿疼痛的生物行为后果。Fischer 344大鼠在出生后的前8天暴露于爪针刺、爪触摸或保持不受干扰，并在成熟时评估对腹部手术或游泳应激的反应。因变量包括：（1）免疫结果：体内自然杀伤（NK）功能，同基因NK敏感性MADB 106肿瘤细胞的肺滞留，以及离体，针对标准YAC-1靶标的全血NK细胞毒性，以及血浆白细胞介素-6;（2）神经内分泌结果：血浆皮质酮和β-内啡肽;以及（3）行为结果，例如旷场测试。该项目的拟议扩展增加了：（1）出生后第一周期间的母仔相互作用，因为这些关系已被证明在应激反应性的发展中发挥作用;（2）肺血管NK细胞对MADB 106肿瘤细胞的活性的体外评估，以反映局部NK细胞抵抗器官特异性转移的能力;（3）全血和肺血管NK细胞的计数，解释肺NK测定的必要性，以及评估每个NK细胞活性变化或每ml全血NK细胞数量变化以解释观察到的全血NK活性差异的手段;和（4）高架十字迷宫测试，以提供额外的和可能更敏感的焦虑测量。这些额外的结果不需要额外的动物，但有可能大幅增加本研究产生的结果，并增强其可解释性。总之，这些额外的结果加强了在新生儿发育过程中反复疼痛经历的负面生理和行为后遗症的可能性。

DESCRIPTION (provided by applicant): Premature and critically ill newborns are among the most vulnerable of populations, requiring intensive nursing care characterized by multiple procedures, many of which are painful. Recent studies in both premature human newborns and neonatal rats provide evidence suggesting that the nervous system is more sensitive to painful stimuli during this time of unparalleled neurosensory plasticity. Given that repetitive nonpainful events in neonatal rats have been shown to affect neuroendocrine and immune responses to stress in mature animals, it is possible that repeated painful stressors might lead to even more profound effects in the mature animal. The overall objective of the funded study is to explore in the mature animal the biobehavioral consequences of repetitive neonatal pain. Fischer 344 rats exposed to either paw needle prick, paw touch or left unperturbed in their first 8 postnatal days and are assessed at maturity for responses to abdominal surgery or swim stress. Dependent variables include: (1) immune outcomes: natural killer (NK) function in vivo, the lung retention of syngeneic NK-sensitive MADB106 tumor cells, and ex-vivo, whole blood NK cytotoxicity against the standard YAC-1 target, and plasma interleukin-6; (2) neuroendocrine outcomes: plasma corticosterone and beta-endorphin; and (3) behavioral outcomes such as open field testing. The proposed expansion of the project adds: (1) maternal-pup interactions during the first postnatal week, as these relationships have been shown to play a role in the development of stress reactivity; (2) ex-vivo assessment of lung vascular NK cell activity against MADB106 tumor cells to reflect the ability of local NK cells to resist an organ-specific metastasis; (3) counts of both whole blood and lung vascular NK cells, a necessity for interpreting the lung NK assay, and a means by which to assess for changes in activity per NK cell or changes in NK cell number per ml whole blood to account for observed differences in whole blood NK activity; and (4) elevated plus-maze testing to provide an additional and possibly more sensitive measure of anxiety. These additional outcomes require no additional animals, yet have the potential to substantially increase the findings produced by this study as well as augment their interpretability. In sum, these additional outcomes strengthen the potential to demonstrate negative physiologic and behavioral sequelae of repeated painful experiences during neonatal development.