Shang Lin, Xu Tian-Le, Li Fei, Su Jiansheng, Li Wei-Guang
Laboratory of Oral Biomedical Science and Translational Medicine, School of Stomatology, Tongji University, Shanghai, 200072, China.
Department of Developmental and Behavioral Pediatrics, Shanghai Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200129, China.
Mol Pain. 2015 Jun 30;11:40. doi: 10.1186/s12990-015-0040-3.
Accumulating clinical and preclinical evidence indicates that chronic pain is often comorbid with persistent low mood and anxiety. However, the mechanisms underlying pain-induced anxiety, such as its causality, temporal progression, and relevant neural networks are poorly understood, impeding the development of efficacious therapeutic approaches.
Here, we have identified the sequential emergence of anxiety phenotypes in mice subjected to dental pulp injury (DPI), a prototypical model of orofacial pain that correlates with human toothache. Compared with sham controls, mice subjected to DPI by mechanically exposing the pulp to the oral environment exhibited significant signs of anxiogenic effects, specifically, altered behaviors on the elevated plus maze (EPM), novelty-suppressed feeding (NSF) tests at 1 but not 3 days after the surgery. Notably, at 7 and 14 days, the DPI mice again avoided the open arm, center area, and novelty environment in the EPM, open field, and NSF tests, respectively. In particular, DPI-induced social phobia and increased repetitive grooming did not occur until 14 days after surgery, suggesting that DPI-induced social anxiety requires a long time. Moreover, oral administration of an anti-inflammatory drug, ibuprofen, or an analgesic agent, ProTx-II, which is a selective inhibitor of NaV1.7 sodium channels, both significantly alleviated DPI-induced avoidance in mice. Finally, to investigate the underlying central mechanisms, we pharmacologically blocked a popular form of synaptic plasticity with a GluA2-derived peptide, long-term depression, as that treatment significantly prevented the development of anxiety phenotype upon DPI.
Together, these results suggest a temporally progressive causal relationship between orofacial pain and anxiety, calling for more in-depth mechanistic studies on concomitant pain and anxiety disorders.
越来越多的临床和临床前证据表明，慢性疼痛常与持续的情绪低落和焦虑并存。然而，疼痛诱发焦虑的潜在机制，如因果关系、时间进程和相关神经网络，目前仍知之甚少，这阻碍了有效治疗方法的开发。
在这里，我们已经确定了在牙髓损伤（DPI）小鼠中焦虑表型的相继出现，DPI是一种与人类牙痛相关的口面部疼痛的典型模型。与假手术对照组相比，通过将牙髓机械暴露于口腔环境而接受DPI的小鼠表现出明显的焦虑效应迹象，具体而言，在手术后1天而非3天，在高架十字迷宫（EPM）、新奇抑制摄食（NSF）试验中行为发生改变。值得注意的是，在第7天和第14天，DPI小鼠在EPM、旷场试验和NSF试验中分别再次避开开放臂、中心区域和新奇环境。特别是，DPI诱导的社交恐惧症和重复梳理行为增加直到手术后14天才出现，这表明DPI诱导的社交焦虑需要很长时间。此外，口服抗炎药布洛芬或镇痛药ProTx-II（一种NaV1.7钠通道的选择性抑制剂）均显著减轻了DPI诱导的小鼠回避行为。最后，为了研究潜在的中枢机制，我们用一种源自GluA2的肽在药理学上阻断了一种常见形式的突触可塑性，即长时程抑制，因为这种治疗显著预防了DPI后焦虑表型的发展。
总之，这些结果表明口面部疼痛与焦虑之间存在时间上渐进的因果关系，这需要对伴随的疼痛和焦虑障碍进行更深入的机制研究。
