Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 21, 2025; 31(23): 103848
Published online Jun 21, 2025. doi: 10.3748/wjg.v31.i23.103848
Endothelin A receptor in nociceptors is essential for persistent mechanical pain in a chronic pancreatitis of mouse model
Bing Wang, Jia-Yi Ge, Jia-Ni Wu, Jia-Huan Xu, Xiao-Hua Cao, Na Chang, Xiang Zhou, Peng-Bo Jing, Xing-Jun Liu, Yong Wu
Bing Wang, Yong Wu, Department of Anesthesiology, The First People’s Hospital of Lianyungang, Lianyungang 222000, Jiangsu Province, China
Jia-Yi Ge, Jia-Ni Wu, Jia-Huan Xu, Xiao-Hua Cao, Na Chang, Xiang Zhou, Peng-Bo Jing, Xing-Jun Liu, School of Pharmacy, Nantong University, Nantong 226019, Jiangsu Province, China
Co-corresponding authors: Xing-Jun Liu and Yong Wu.
Author contributions: Wang B and Liu XJ designed and coordinated the study; Wang B, Ge JY, Wu JN, Xu JH, Cao XH, Chang N, Zhou X, and Jing PB performed the experiments, acquired and analyzed data; Wang B, Liu XJ, and Wu Y interpreted the data; Liu XJ and Wu Y contributed equally as co-corresponding authors; Wang B and Wu Y wrote the manuscript; and all authors approved the final version of the article.
Supported by Hansoh Foundation of Lianyungang, No. QN1913.
Institutional animal care and use committee statement: All animal studies were performed based on relevant ethical guidelines of the International Association for the Study of Pain and approved by the Committees of the Use of Laboratory Animals of Nantong University (Approval No. S20220217-016).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for 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: sharing statement: No additional data are available.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Yong Wu, MD, Chief Physician, Department of Anesthesiology, The First People’s Hospital of Lianyungang, No. 6 Zhenhua East Street, Lianyungang 222000, Jiangsu Province, China. 18961325621@163.com
Received: December 4, 2024
Revised: March 30, 2025
Accepted: May 30, 2025
Published online: June 21, 2025
Processing time: 200 Days and 1.7 Hours
Abstract
BACKGROUND

Chronic pancreatitis (CP) accompanied with persistent abdominal pain represents a major clinical challenge for the symptom management in patients. Although with clear involvement of neuropathy, the detailed mechanisms underlying pain hypersensitivity associated with CP are not totally clear. The endothelin system has been reported to contribute to chronic pain and chronic inflammatory settings, and is a potential therapeutic target for the treatment of chronic pain.

AIM

To evaluate the role of nociceptor-specific endothelin A receptor (ETAR) in pain hypersensitivity in a CP mouse model and its potential contributing mechanisms.

METHODS

Oral gavage delivery of dibutyltin dichloride (DBTC) was used to induce CP in mice. A conditional knockout (CKO) strain which specifically delete ETAR in dorsal root ganglion (DRG) nociceptive neurons was generated. Abdominal pain hypersensitivity associated with CP and other behaviors were evaluated. The size of mouse gallbladder was measured and pancreatic histopathology was examined to validate the CP model. Calcitonin gene-related peptide expression and immune cells in the innervated DRGs and spinal cord were also examined. Calcium imaging in dissociated DRG neurons was performed to investigate the excitability of affected nociceptive neurons.

RESULTS

Specific deletion of endothelin receptor type A gene in nociceptive DRG neurons did not affect basal abdominal thermal and mechanical pain threshold in mice. Abdominal mechanical pain hypersensitivity was persistent in DBTC-treated WT mice but was significantly reduced in DBTC-treated CKO mice. DBTC treatment did not affect mouse nociceptive responses to heat and cold stimuli, as well as motor functions and anxiety-like behaviors of mice. DBTC treatment induced severe pancreatic inflammation and obvious gallbladder enlargement in wild type (WT) mice, but less in CKO mice. DBTC-induced increase of calcitonin gene-related peptide- and induction of brown adipocytes 1-positive signals in the DRG and spinal cord in WT mice were remarkably attenuated in CKO mice. DRG neurons from CKO mice exhibited less excitability and sensitivity in response to endothelin-1 exposure than those from WT mice.

CONCLUSION

DBTC intragastric administration in mice produced a convenient and reliable animal model for studying abdominal pain associated with CP. ETAR-dependent endothelin signaling in nociceptors is important for the development of persistent abdominal mechanical hypersensitivity in mice.

Keywords: Chronic pancreatitis; Abdominal pain; Endothelin; Endothelin A receptor; Calcitonin gene-related peptide; Macrophage infiltration; Microglia activation

Core Tip: Currently the mechanism underlying abdominal pain associated with chronic pancreatitis (CP) is not well understood. Utilizing dibutyltin dichloride-induced CP mouse model, it was found that the nociceptor-expressing endothelin A receptor (ETAR) is essential for the development of mechanical hypersensitivity following dibutyltin dichloride treatment. ETAR may contribute to this through regulating calcitonin gene-related peptide expression and activating immune cells. Therefore, targeting ETAR-dependent endothelin signaling in nociceptive sensory neurons may be a potential therapeutic approach for treating CP patients.