Anseloni V C Z, He F, Novikova S I, Turnbach Robbins M, Lidow I A, Ennis M, Lidow M S
Department of Biomedical Sciences, University of Maryland, 666 West Baltimore Street, Baltimore, MD 21201, USA.
Neuroscience. 2005;131(3):635-45. doi: 10.1016/j.neuroscience.2004.11.039.
Recently, there has been a growing interest in long-term consequences of neonatal pain because modern neonatal intensive care units routinely employ procedures that cause considerable pain and may be followed by local inflammation and hyperalgesia lasting for several hours or even days. To address this question, we developed a rat model of short lasting (<2 days) early local inflammatory insult produced by a single injection of 0.25% carrageenan (CAR) into the plantar surface of a hindpaw. Previously, we demonstrated that rats receiving this treatment within the first week after birth grow into adults with a global reduction in responsiveness to acute pain. Here, we report that these animals also manifest a low anxiety trait associated with reduced emotional responsiveness to stress. This conclusion is based in the following observations: (a) rats in our model display reduced anxiety on an elevated plus-maze; (b) in the forced swim test, these rats exhibit behavioral characteristics associated with stronger ability for stress coping; and (c) these animals have reduced basal and stress-induced plasma levels of such stress-related neuroendocrine markers as corticotropin-releasing factor, vasopressin, and adrenocorticotrophic hormone. In addition, we used DNA microarray and real-time reverse-transcriptase polymerase chain reaction to profile long-term changes in gene expression in the midbrain periaqueductal gray (PAG; a region involved in both stress and pain modulation) in our animal model. Among the affected genes, serotonergic receptors were particularly well represented. Specifically, we detected increase in the expression of 5-HT1A, 5-HT1D, 5-HT2A, 5-HT2C and 5-HT4 receptors. Several of these receptors are known to be involved in the anxiolytic and analgesic activity of the PAG. Finally, to determine whether neonatal inflammatory insult induces elevation in maternal care, which may play a role in generating long-term behavioral alterations seen in our model, we examined maternal behavior for 3 days following CAR injection. Indeed, we observed a substantial increase in maternal attention to the pups at the time of inflammation, but this increase was not without its cost: a period of significant maternal neglect afterward.
最近，人们对新生儿疼痛的长期后果越来越感兴趣，因为现代新生儿重症监护病房经常采用会引起相当大疼痛的操作，并且之后可能会出现持续数小时甚至数天的局部炎症和痛觉过敏。为了解决这个问题，我们建立了一种大鼠模型，通过在后爪足底单次注射0.25%角叉菜胶（CAR）产生短期（<2天）的早期局部炎症损伤。此前，我们证明在出生后第一周接受这种治疗的大鼠成年后对急性疼痛的反应性整体降低。在此，我们报告这些动物还表现出与对应激的情绪反应降低相关的低焦虑特质。这一结论基于以下观察结果：（a）我们模型中的大鼠在高架十字迷宫中表现出焦虑减轻；（b）在强迫游泳试验中，这些大鼠表现出与更强应激应对能力相关的行为特征；（c）这些动物基础和应激诱导的血浆中促肾上腺皮质激素释放因子、血管加压素和促肾上腺皮质激素等应激相关神经内分泌标志物水平降低。此外，我们使用DNA微阵列和实时逆转录聚合酶链反应来分析我们动物模型中中脑导水管周围灰质（PAG；一个参与应激和疼痛调节的区域）基因表达的长期变化。在受影响的基因中，血清素能受体特别突出。具体而言，我们检测到5-HT1A、5-HT1D、5-HT2A、5-HT2C和5-HT4受体的表达增加。其中一些受体已知参与PAG的抗焦虑和镇痛活性。最后，为了确定新生儿炎症损伤是否会导致母性关怀增加，而母性关怀可能在产生我们模型中所见的长期行为改变中起作用，我们在注射CAR后3天检查了母性行为。事实上，我们观察到在炎症发生时母鼠对幼崽的关注度大幅增加，但这种增加并非没有代价：之后会有一段明显的母性忽视期。
