Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 28, 2019; 25(40): 6077-6093
Published online Oct 28, 2019. doi: 10.3748/wjg.v25.i40.6077
Nucleus tractus solitarius mediates hyperalgesia induced by chronic pancreatitis in rats
Yang Bai, Ying-Biao Chen, Xin-Tong Qiu, Yan-Bing Chen, Li-Tian Ma, Ying-Qi Li, Hong-Ke Sun, Ming-Ming Zhang, Ting Zhang, Tao Chen, Bo-Yuan Fan, Hui Li, Yun-Qing Li
Yang Bai, Xin-Tong Qiu, Yan-Bing Chen, Li-Tian Ma, Ming-Ming Zhang, Ting Zhang, Tao Chen, Hui Li, Yun-Qing Li, Department of Anatomy, Histology and Embryology & K. K. Leung Brain Research Centre, Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
Ying-Biao Chen, Department of Anatomy, Fujian Health College, Fuzhou 350101, Fujian Province, China
Ying-Qi Li, Hong-Ke Sun, Bo-Yuan Fan, Department of Cardiology, The Second Affiliated Hospital of Xian Jiaotong University, Xian Jiaotong University, Xi'an 710004, Shaanxi Province, China
Yun-Qing Li, Joint Laboratory of Neuroscience at Hainan Medical University and Fourth Military Medical University, Hainan Medical University, Haikou 571199, Hainan Province, China
Author contributions: Bai Y and Chen YB established the CP model, performed behavior tests, and harvested tissue samples; Chen YB and Chen T performed electrophysiological tests; Ma LT, Li YQ, and Sun HK carried out immunoblotting tests; Bai Y, Zhang T, and Qiu XT performed immunostaining tests; Li YQ, Li H and Fan BY designed the study and edited the manuscript; Bai Y analyzed the data and wrote the manuscript; Bai Y and Chen YB contributed equally to this manuscript.
Supported by National Natural Science Foundation of China, No. 81620108008; Major Research and Development Project of Hainan Province, No. 2018153 to Yun-Qing Li; and Training Program for Scientific Research Scholars of Fujian Provincial Health and Family Planning Commission, No. 2018-ZQN-74 to Ying-Biao Chen.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Fourth Military Medical University (IACUC protocol number: 20170702).
Conflict-of-interest statement: The authors declare that there are no competing financial interests.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This 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 Non Commercial (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:
Corresponding author: Yun-Qing Li, PhD, Professor, Department of Anatomy, Histology and Embryology & K. K. Leung Brain Research Centre, Fourth Military Medical University, No. 169, West Changle Road, Xi'an 710032, Shaanxi Province, China.
Telephone: +86-29-84772706 Fax: +86-29-83283229
Received: July 17, 2019
Peer-review started: July 19, 2019
First decision: August 18, 2019
Revised: September 6, 2019
Accepted: September 11, 2019
Article in press: September 11, 2019
Published online: October 28, 2019

Central sensitization plays a pivotal role in the maintenance of chronic pain induced by chronic pancreatitis (CP). We hypothesized that the nucleus tractus solitarius (NTS), a primary central site that integrates pancreatic afferents apart from the thoracic spinal dorsal horn, plays a key role in the pathogenesis of visceral hypersensitivity in a rat model of CP.


To investigate the role of the NTS in the visceral hypersensitivity induced by chronic pancreatitis.


CP was induced by the intraductal injection of trinitrobenzene sulfonic acid (TNBS) in rats. Pancreatic hyperalgesia was assessed by referred somatic pain via von Frey filament assay. Neural activation of the NTS was indicated by immunohistochemical staining for Fos. Basic synaptic transmission within the NTS was assessed by electrophysiological recordings. Expression of vesicular glutamate transporters (VGluTs), N-methyl-D-aspartate receptor subtype 2B (NR2B), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subtype 1 (GluR1) was analyzed by immunoblotting. Membrane insertion of NR2B and GluR1 was evaluated by electron microscopy. The regulatory role of the NTS in visceral hypersensitivity was detected via pharmacological approach and chemogenetics in CP rats.


TNBS treatment significantly increased the number of Fos-expressing neurons within the caudal NTS. The excitatory synaptic transmission was substantially potentiated within the caudal NTS in CP rats (frequency: 5.87 ± 1.12 Hz in CP rats vs 2.55 ± 0.44 Hz in sham rats, P < 0.01; amplitude: 19.60 ± 1.39 pA in CP rats vs 14.71 ± 1.07 pA in sham rats; P < 0.01). CP rats showed upregulated expression of VGluT2, and increased phosphorylation and postsynaptic trafficking of NR2B and GluR1 within the caudal NTS. Blocking excitatory synaptic transmission via the AMPAR antagonist CNQX and the NMDAR antagonist AP-5 microinjection reversed visceral hypersensitivity in CP rats (abdominal withdraw threshold: 7.00 ± 1.02 g in CNQX group, 8.00 ± 0.81 g in AP-5 group and 1.10 ± 0.27 g in saline group, P < 0.001). Inhibiting the excitability of NTS neurons via chemogenetics also significantly attenuated pancreatic hyperalgesia (abdominal withdraw threshold: 13.67 ± 2.55 g in Gi group, 2.00 ± 1.37 g in Gq group, and 2.36 ± 0.67 g in mCherry group, P < 0.01).


Our findings suggest that enhanced excitatory transmission within the caudal NTS contributes to pancreatic pain and emphasize the NTS as a pivotal hub for the processing of pancreatic afferents, which provide novel insights into the central sensitization of painful CP.

Keywords: Rat, Chronic pancreatitis, Visceral hypersensitivity, Nucleus tractus solitarius, Excitatory synaptic transmission

Core tip: This study investigated the role of the nucleus tractus solitarius (NTS) in the pathogenesis of visceral hypersensitivity in a rat model of chronic pancreatitis (CP). We demonstrated that CP rats exhibited potentiated excitatory synaptic transmission within the caudal NTS. This potentiation may be mediated by enhanced glutamate release and the recruitment of membrane glutamate receptors. Inhibiting both the excitatory synaptic transmission and neural activity of caudal NTS neurons alleviated visceral hypersensitivity in CP rats. Our results suggest the caudal NTS as a primary central site that processes pancreatic pain, as well as a potential therapeutic target for the treatment of chronic visceral pain in patients with CP.