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©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
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: http://creativecommons.org/licenses/by-nc/4.0/
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.
deptanat@fmmu.edu.cn
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
Processing time: 102 Days and 12.2 Hours
ARTICLE HIGHLIGHTS
Research background
Central sensitization plays a pivotal role in the maintenance of chronic pain induced by chronic pancreatitis (CP). Previous studies concerning the central processing of painful CP usually center on the spinal dorsal horn. However, much less focus has been directed on the nucleus tractus solitarius (NTS), another primary central site for pancreatic afferents, during painful CP.
Research motivation
We aimed to investigate the plastic changes of caudal NTS as well as its role in the development of painful CP in rats.
Research methods
Chronic pancreatitis was established by intraductal injection of trinitrobenzene sulfonic acid (TNBS) in rats. Abdomen mechanical hypersensitivity was assessed by von Frey filament test. Then, immunohistochemical staining for Fos was performed to lay morphological evidence for NTS activation during painful CP, while patch-clamp recordings were performed to explore the changes of basic excitatory transmission of NTS in CP rats. Next, the expression of VGluT1, NMDAR subunit NR2B, and AMPAR subunit GluR1 was analyzed by immunoblottings. Membrane insertion of NR2B and GluR1 was evaluated by electron microscopy. Finally, AMPAR antagonist CNQX or NMDAR antagonist AP-5 was microinjected into the NTS to block the glutamatergic transmission on postoperative day (POD) 14 and then abdominal withdraw threshold (AWT) was tested. Chemogenetic method was also utilized to activate or inhibit the activity of excitatory NTS neurons on POD 14 and then AWT was tested.
Research results
TNBS treatment increased the number of Fos-expressing neurons within the caudal NTS. Both the frequency and amplitude of sEPSC of second-order neurons within the caudal NTS were substantially potentiated in CP rats. TNBS treatment upregulated the expression of VGluT2, and enhanced the phosphorylation and postsynaptic trafficking of NR2B and GluR1 within the caudal NTS. Blocking excitatory synaptic transmission increased the AWT of CP rats. Chemogenetic inhibition of the excitability of excitatory NTS neurons also significantly attenuated pancreatic hyperalgesia.
Research conclusions
These data suggest that both presynaptic and postsynaptic mechanisms contribute to the enhanced excitatory transmission within the caudal NTS, which mediates visceral hypersensitivity under the condition of painful CP.
Research perspectives
The results obtained deepen our understanding of central sensitization in pancreatic pain and support the caudal NTS, apart from the thoracic spinal cord, as another important central site for the processing of pancreatic pain, which may provide new clues for gastroenterologists and pain physicians in the treatment of CP.
