Tail clamping induces anxiety-like behaviors and visceral hypersensitivity in rat models of non-erosive reflux disease

doi:10.5498/wjp.v16.i1.112432

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World Journal of Psychiatry

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World J Psychiatry. Jan 19, 2026; 16(1): 112432
Published online Jan 19, 2026. doi: 10.5498/wjp.v16.i1.112432

Tail clamping induces anxiety-like behaviors and visceral hypersensitivity in rat models of non-erosive reflux disease

Mi Lv, Xin Liu, Kai-Yue Huang, Yu-Xi Wang, Zheng Wang, Li-Li Han, Hui Che, Lin Lv, Feng-Yun Wang

Mi Lv, Kai-Yue Huang, Li-Li Han, Hui Che, Lin Lv, Feng-Yun Wang, Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China

Xin Liu, Yu-Xi Wang, Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China

Zheng Wang, Department of Gastroenterology, Peking University Health Science Center, Beijing 100191, China

Co-corresponding authors: Lin Lv and Feng-Yun Wang.

Author contributions: Lv M, Lv L, and Wang FY conceived and designed the study; Lv M coordinated the experimental procedures and data collection; Liu X and Huang KY performed statistical analyses and data interpretation; Che H, Han LL, and Wang YX contributed to model validation and quality control; Wang Z and Lv L assisted with experimental operations and animal model preparation; all authors participated in manuscript drafting, critical revision, and final approval of the submitted version; Wang FY and Lv L contributed equally to this work as co-corresponding authors; Wang FY is designated as the primary corresponding author responsible for all communication during the manuscript submission, peer-review, and publication process, including ensuring that all administrative requirements of the journal are properly fulfilled.

Supported by the National Key Specialty of Traditional Chinese Medicine (Spleen and Stomach Diseases), No. 0500004; National Natural Science Foundation of China, No. 82205104 and No. 82104850; Hospital Capability Enhancement Project of Xiyuan Hospital, CACMS, No. XYZX0303-07; and the Fundamental Research Funds for the Central Public Welfare Research Institutes, Excellent Young Scientists Training Program of China Academy of Chinese Medical Sciences, No. ZZ16-YQ-002.

Institutional review board statement: The human subject study was reviewed and approved by the Institutional Review Board of Xiyuan Hospital, China Academy of Chinese Medical Sciences (Approval ID: 2024XLA247-2).

Institutional animal care and use committee statement: All animal procedures were reviewed and approved by the Institutional Animal Care and Use Committee of the same institution (IACUC protocol number: 2024XLC101-2).

Conflict-of-interest statement: The authors have no competing interests to declare that are relevant to the content of this article.

ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.

Data sharing statement: The data reported in this study can be obtained from the corresponding author upon reasonable request.

Corresponding author: Feng-Yun Wang, MD, Chief Physician, Professor, Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, No. 1 Xiyuan Playground, Haidian District, Beijing 100091, China. 18810631761@163.com

Received: July 28, 2025
Revised: August 30, 2025
Accepted: October 22, 2025
Published online: January 19, 2026
Processing time: 156 Days and 23.5 Hours

Abstract

BACKGROUND

Non-erosive reflux disease (NERD), the main gastroesophageal reflux subtype, features reflux symptoms without mucosal damage. Anxiety links to visceral hypersensitivity in NERD, yet mechanisms and animal models are unclear.

AIM

To establish a translational NERD rat model with anxiety comorbidity via tail clamping and study corticotropin-releasing hormone (CRH)-mediated neuroimmune pathways in visceral hypersensitivity and esophageal injury.

METHODS

Sprague-Dawley (SD) and Wistar rats were grouped into sham, model, and modified groups (n = 10 each). The treatments for the modified groups were as follows: SD rats received ovalbumin/aluminum hydroxide suspension + acid perfusion ± tail clamping (40 minutes/day for 7 days), while Wistar rats received fructose water + tail clamping. Esophageal pathology, visceral sensitivity, and behavior were assessed. Serum CRH, calcitonin gene-related peptide (CGRP), 5-hydroxytryptamine (5-HT), and mast cell tryptase (MCT) and central amygdala (CeA) CRH mRNA were measured via ELISA and qRT-PCR.

RESULTS

Tail clamping induced anxiety, worsening visceral hypersensitivity (lower abdominal withdrawal reflex thresholds, P < 0.05) and esophageal injury (dilated intercellular spaces and mitochondrial edema). Both models showed raised serum CRH, CGRP, 5-HT, and MCT (P < 0.01) and CeA CRH mRNA expression (P < 0.01). Behavioral tests confirmed anxiety-like phenotypes. NERD-anxiety rats showed clinical-like symptom severity without erosion.

CONCLUSION

Tail clamping induces anxiety in NERD models, worsening visceral hypersensitivity via CRH neuroimmune dysregulation, offering a translational model and highlighting CRH as a treatment target.

Keywords: Non-erosive reflux disease; Anxiety and depression; Animal model; Tail-clamping; Corticotropin hormones

Core Tip: This study systematically compares two non-surgical modeling approaches, ovalbumin (OVA)/aluminum hydroxide suspension [Al(OH)₃] + acid perfusion vs fructose water + tail clamping, for non-erosive reflux disease (NERD). It demonstrates that a 7-day tail clamping protocol effectively induces anxiety-like behaviors and exacerbates visceral hypersensitivity through corticotropin-releasing hormone-mediated neuroimmune pathways. The modified OVA/Al(OH)₃ model combined with tail clamping can serve as an efficient platform for investigating brain-gut interactions in NERD with psychiatric comorbidity. This novel approach offers significant advantages over traditional chronic stress methods in terms of both induction efficiency (requiring only 40 minutes/day for 7 days) and pathological reproducibility.