Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA.
Pain. 2010 Nov;151(2):540-549. doi: 10.1016/j.pain.2010.08.029. Epub 2010 Sep 17.
Inflammation or pain during neonatal development can result in long-term structural and functional alterations of nociceptive pathways, ultimately altering pain perception in adulthood. We have developed a mouse model of neonatal colon irritation (NCI) to investigate the plasticity of pain processing within the viscerosensory system. Mouse pups received an intracolonic administration of 2% mustard oil (MO) on postnatal days 8 and 10. Distal colons were processed at subsequent timepoints for myeloperoxidase (MPO) activity and growth factor expression. Adult mice were assessed for visceral hypersensitivity by measuring the visceromotor response during colorectal distension. Dorsal root ganglion (DRG) neurons from adult mice were retrogradely labeled from the distal colon and calcium imaging was used to measure transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) responses to acute application of capsaicin and MO, respectively. Despite the absence of inflammation (as indicated by MPO activity), neonatal exposure to intracolonic MO transiently maintained a higher expression level of growth factor messenger RNA (mRNA). Adult NCI mice displayed significant visceral hypersensitivity, as well as increased sensitivity to mechanical stimulation of the hindpaw, compared to control mice. The percentage of TRPA1-expressing colon afferents was significantly increased in NCI mice, however they displayed no increase in the percentage of TRPV1-immunopositive or capsaicin-sensitive colon DRG neurons. These results suggest that early neonatal colon injury results in a long-lasting visceral hypersensitivity, possibly driven by an early increase in growth factor expression and maintained by permanent changes in TRPA1 function.
在新生儿发育过程中的炎症或疼痛可导致伤害性通路的长期结构和功能改变，最终改变成年后的疼痛感知。我们开发了一种新生鼠结肠刺激（NCI）模型，以研究内脏感觉系统中疼痛处理的可塑性。新生鼠在出生后第 8 天和第 10 天接受 2%芥子油（MO）的结肠内给药。在随后的时间点，对远端结肠进行髓过氧化物酶（MPO）活性和生长因子表达的检测。通过测量结直肠扩张期间的内脏运动反应来评估成年小鼠的内脏高敏感性。从成年小鼠的背根神经节（DRG）神经元中逆行标记远端结肠，并使用钙成像来测量瞬时受体电位香草酸 1（TRPV1）和ankyrin 1（TRPA1）对辣椒素和 MO 的急性应用的反应。尽管缺乏炎症（如 MPO 活性所示），但新生鼠暴露于结肠内 MO 会短暂地维持生长因子信使 RNA（mRNA）的更高表达水平。与对照小鼠相比，成年 NCI 小鼠表现出显著的内脏高敏感性，以及对后爪机械刺激的敏感性增加。NCI 小鼠中表达 TRPA1 的结肠传入神经元的百分比显著增加，但 TRPV1 免疫阳性或辣椒素敏感的结肠 DRG 神经元的百分比没有增加。这些结果表明，早期新生鼠结肠损伤导致持久的内脏高敏感性，可能由早期生长因子表达的增加驱动，并由 TRPA1 功能的永久变化维持。
