Laboratory of Neuroimmunology, School of Psychology, University of Newcastle, Newcastle, New South Wales, Australia; School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia; Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.
Brain Behav Immun. 2015 Feb;44:235-46. doi: 10.1016/j.bbi.2014.10.014. Epub 2014 Oct 31.
The immune and nociceptive systems are shaped during the neonatal period where they undergo fine-tuning and maturation. Painful experiences during this sensitive period of development are known to produce long-lasting effects on the immune and nociceptive responses. It is less clear, however, whether inflammatory pain responses are primed by neonatal exposure to mild immunological stimuli, such as with lipopolysaccharide (LPS). Here, we examine the impact of neonatal LPS exposure on inflammatory pain responses, peripheral and hippocampal interleukin-1β (IL-1β), as well as mast cell number and degranulation in preadolescent and adult rats. Wistar rats were injected with LPS (0.05mg/kg IP, Salmonella enteritidis) or saline on postnatal days (PNDs) 3 and 5 and later subjected to the formalin test at PNDs 22 and 80-97. At both time-points, and one-hour after formalin injection, blood and hippocampus were collected for measuring circulating and central IL-1β levels using ELISA and Western blot, respectively. Paw tissue was also isolated to assess mast cell number and degree of degranulation using Toluidine Blue staining. Behavioural analyses indicate that at PND 22, LPS-challenged rats displayed enhanced flinching (p<.01) and licking (p<.01) in response to formalin injection. At PNDs 80-97, LPS-challenged rats exhibited increased flinching (p<.05), an effect observed in males only. Furthermore, neonatal LPS exposure enhanced circulating IL-1β and mast cell degranulation in preadolescent but not adult rats following formalin injection. Hippocampal IL-1β levels were increased in LPS-treated adult but not preadolescent rats in response to formalin injection. These data suggest neonatal LPS exposure produces developmentally regulated changes in formalin-induced behavioural responses, peripheral and central IL-1β levels, as well as mast cell degranulation following noxious stimulation later in life. These findings highlight the importance of immune activation during the neonatal period in shaping immune response and pain sensitivity later in life. This is of clinical relevance given the high prevalence of bacterial infection during the neonatal period, particularly in the vulnerable population of preterm infants admitted to neonatal intensive care units.
免疫系统和伤害感受系统在新生儿期形成，在此期间它们经历精细调节和成熟。已知在发育的这个敏感时期经历疼痛会对免疫和伤害感受反应产生持久影响。然而，新生儿暴露于轻度免疫刺激物（如脂多糖 [LPS]）是否会引发炎症性疼痛反应尚不清楚。在这里，我们研究了新生儿 LPS 暴露对炎症性疼痛反应、外周和海马白细胞介素-1β（IL-1β）以及小胶质细胞数量和脱颗粒的影响在未成年和成年大鼠中。Wistar 大鼠在出生后第 3 天和第 5 天分别接受 LPS（0.05mg/kg IP，肠炎沙门氏菌）或生理盐水注射，然后在第 22 天和第 80-97 天接受福尔马林测试。在这两个时间点，以及福尔马林注射后一小时，收集血液和海马组织，分别使用 ELISA 和 Western blot 测量循环和中枢 IL-1β 水平。还分离爪子组织，使用甲苯胺蓝染色评估小胶质细胞数量和脱颗粒程度。行为分析表明，在第 22 天，LPS 挑战的大鼠对福尔马林注射表现出增强的退缩（p<.01）和舔舐（p<.01）。在第 80-97 天，LPS 挑战的大鼠表现出退缩增加（p<.05），这种影响仅在雄性中观察到。此外，在未成年大鼠和成年大鼠中，新生儿 LPS 暴露增强了福尔马林注射后的循环 IL-1β 和小胶质细胞脱颗粒。福尔马林注射后，LPS 处理的成年大鼠而非未成年大鼠的海马 IL-1β 水平升高。这些数据表明，新生儿 LPS 暴露会导致甲醛诱导的行为反应、外周和中枢 IL-1β 水平以及伤害性刺激后小胶质细胞脱颗粒发生发育调节变化。这些发现强调了新生儿期免疫激活在塑造生命后期免疫反应和疼痛敏感性方面的重要性。考虑到新生儿期细菌感染的高发率，特别是在入住新生儿重症监护病房的早产儿脆弱人群中，这一点具有临床意义。
