title: Temporal dynamics of anxiety phenotypes in a dental pulp injury model.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Oral Biomedical Science and Translational Medicine, School of Stomatology, Tongji University, Shanghai, 200072, China. shanglin7777@gmail.com.|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. shanglin7777@gmail.com.|Discipline of Neuroscience and Department of Anatomy, Histology and Embryology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China. shanglin7777@gmail.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Shang
authors.affiliation: Discipline of Neuroscience and Department of Anatomy, Histology and Embryology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China. xu-happiness@shsmu.edu.cn.
authors.forename: Tian-Le
authors.initials: TL
authors.lastname: Xu
authors.affiliation: 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. feili@shsmu.edu.cn.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: Laboratory of Oral Biomedical Science and Translational Medicine, School of Stomatology, Tongji University, Shanghai, 200072, China. sjs@tongji.edu.cn.
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Su
authors.affiliation: Discipline of Neuroscience and Department of Anatomy, Histology and Embryology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China. wgli@shsmu.edu.cn.
authors.forename: Wei-Guang
authors.initials: WG
authors.lastname: Li
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D001522:Behavior, Animal; D003782:Dental Pulp / Q000187:drug effects / Q000293:injuries* / Q000503:physiopathology; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D006801:Humans; D007052:Ibuprofen / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D059225:Nociception / Q000187:drug effects; D010147:Pain Measurement; D010641:Phenotype; D012919:Social Behavior; D013111:Spider Venoms / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; C470626:ProTx-II peptide; D013111:Spider Venoms; D007052:Ibuprofen