Published online Nov 14, 2017. doi: 10.3748/wjg.v23.i42.7594
Peer-review started: July 28, 2017
First decision: September 26, 2017
Revised: October 4, 2017
Accepted: October 18, 2017
Article in press: October 19, 2017
Published online: November 14, 2017
Functional dyspepsia (FD) is a common gastrointestinal disorder that is characterized by persistent or recurrent upper abdominal pain or discomfort in the absence of any structural, morphological or known organic abnormality, often accompanied by psychosocial disturbance. Gastric hypersensitivity (GHS) is one of the characteristic pathogeneses of FD and represents a cardinal pathophysiological change in FD. Clinical studies have shown that approximately 35%-65% of FD patients suffer from GHS, and among them, 10%-25% have been confirmed to have GHS-related postprandial epigastric pain. Anxiety is a common psycho-social disturbance and troubles 40%-90% of the FD patients in clinic. Various studies have suggested that anxiety may influence gastric sensitivity, gastrointestinal movement, gastric emptying and gut neuroendocrine regulation. However, although GHS and anxiety have been identified as important factors triggering or aggravating FD, the mechanisms by which affect the development of FD and the relationship between them are still unknown. In part, this is due to a lack of both available visceral tissue from FD patients and normal human subjects and suitable animal models of FD with anxiety. Therefore, in order to elucidate the pathogenesis of FD and develop new drugs for the treatment of FD, creating a novel animal model of FD with anxiety-like GHS is of vital importance.
The research motivation came from the reality that there are no defined approaches in rat models that simultaneously mimic anxiety-like behaviors and GHS of FD in a standardized way yet. The authors tried to solve this problem by making rats undergo stress early in life and late in adulthood. The authors believed that the establishment of this rat model would be useful to explore the pathogenesis of FD and to develop new drugs for use FD treatment in the future.
The main objective of this study was to develop a new rat model of anxiety-like GHS of FD by the method of novel sequential stress. The results showed that the authors have realized this objective initially. Its significance lies in that researchers will have a new choice in the study of the pathogenesis of FD and in the development of new drugs.
In order to create this rat model successfully, the authors took a method of novel sequential stress. It includes maternal separation (MS) and acute gastric irritation (AGI) early in life and restraint stress (RS) in adulthood. Furthermore, the authors used the elevated plus maze, open field experiment, abdominal withdrawal reflex testing and electromyographic recordings to evaluate the rat’s behavioral characteristics. Finally, the alterations of several anxiety-related brain-stomach modulators including 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA), brain-derived neurotrophic factor (BDNF) and nesfatin-1 in the rat hippocampus, plasma and gastric fundus and the 5-HT1A receptor (5-HT1AR) in the hippocampal CA1 subfield and the mucosa of the gastric fundus were examined.
The results showed that the sequential-stress-treated rats simultaneously demonstrated anxiety-like behaviors and GHS compared with the control group. Their rate of gastric emptying was also lower than the control group. Furthermore, sequential stress could significantly decrease the levels of 5-HT, GABA and BDNF in the hippocampus but increase the content of nesfatin-1 in the same site; significantly decrease the levels of 5-HT and BDNF in the plasma but increase the content of nesfatin-1 in it; significantly decrease the levels of 5-HT and BDNF in the gastric fundus but increase the content of nesfatin-1 in the same site. The expressions of 5-HT1AR in the hippocampal CA1 subfield and the mucosa of the gastric fundus were down-regulated. The contribution of this study, as is thought by the authors, is that it provided a novel rat model of FD with anxiety-like GHS to the research in this field and partly explored the molecular mechanisms of this important disease. However, there are still many complicated problems such as the relationship between anxiety-like GHS of FD and hypothalamic-pituitary-adrenal axis to be solved in the future.
A method of sequential stress, namely, MS and AGI early in life followed by RS in adulthood, were firstly adopted in creating a rat model of anxiety-like GHS of FD, which could mimic the phenomenon observed in clinic that adverse physiological or psychosocial experiences in early life and acute stress in adulthood are linked to the development of FD. The results also showed the alterations of several anxiety-related neurobiochemical modulators in brain-blood-stomach axis such as 5-HT, GABA, BDNF and nesfatin-1, and thus further deepened the understanding of the molecular mechanisms of FD. Besides, this study supplied a possible tool for the development of new drugs in the treatment of FD.
While doing this study the operation of the implantation of gastric balloon and electrodes is very important in creating this novel rat model of FD with anxiety-like GHS. The direction of the future research in this field lies in the investigation of the molecular mechanisms of the psychological and pathophysiological abnormalities in brain-gut interaction of this important clinical problem and the development of new drugs using this model.