Irritable bowel syndrome (IBS) is a prevalent digestive issue with unknown causes that impacts approximately 10% of people worldwide. Recent research suggests that opioid delta-receptor agonists may help ease IBS symptoms by directly influencing the central nervous system. A unique mouse model that simulates stress was utilized in the study, showing that these medications can lessen abdominal discomfort and control bowel movements. This finding opens up a potential new pathway for IBS treatment by addressing stress as a key factor.
Irritable bowel syndrome (IBS) is a widespread digestive disorder affecting the intestines, leading to symptoms such as belly pain, bloating, gas, and various bowel changes, including diarrhea, constipation, or a mix of both. While this condition impacts roughly 10% of the world’s population, the precise causes and mechanisms behind IBS remain elusive. As a result, treatment strategies mainly concentrate on alleviating symptoms rather than tackling the underlying problem.
At the Tokyo University of Science (TUS) in Japan, Professor Akiyoshi Saitoh and his research team have dedicated the last ten years to examining this subject. Their study, published online in the British Journal of Pharmacology on December 25, 2024, revealed that a category of drugs known as opioid delta-receptor (DOP) agonists might assist in reducing IBS symptoms by targeting the central nervous system instead of the intestine directly. This research was co-authored by Toshinori Yoshioka, a third-year PhD student at TUS.
A key driving factor for this investigation was the accumulating evidence linking IBS to psychological stress. Saitoh’s team aimed to tackle this potential primary cause by creating a new animal model for IBS. In a 2022 publication, they established a mouse model subjected to repeated psychological stress through a technique called chronic vicarious social defeat stress (cVSDS), which elicited symptoms akin to a variant of IBS known as IBS-D. These symptoms included increased intestinal activity and greater sensitivity to abdominal discomfort, despite no physical damage being evident in the organs. The cVSDS model involved having the subject mouse observe a dominant, aggressive mouse repeatedly overpowering a cage mate, causing indirect chronic stress.
Employing the cVSDS model, the researchers investigated whether DOP in the brain, known to be associated with pain and mood control, could serve as key pharmaceutical targets for managing stress-associated IBS. They conducted numerous rigorous experiments to analyze the effects of DOP agonists on IBS indicators and brain chemical signaling. Some experiments assessed the transit speed of a charcoal meal through the gut to measure gastrointestinal movement and evaluate the impacts of stress or treatment on bowel speed, alongside direct measurements of neurotransmitter levels via in vivo brain microdialysis. These studies showed that re-exposure to VSDS raised glutamate levels in the insular cortex, but these spikes were normalized with DOP agonists.
The findings indicated that administering DOP agonists significantly alleviated abdominal pain and helped regulate intestinal movements in cVSDS mice. Notably, applying DOP agonists directly to a certain area of the brain called the insular cortex produced effects on IBS symptoms comparable to systemic treatments. “Our results demonstrated that DOP agonists acted directly within the central nervous system to improve symptoms of diarrhea-predominant IBS in mice, suggesting that their mechanism of action involves the regulation of glutamate neurotransmission in the insular cortex,” states Saitoh.
In summary, the ongoing research by Saitoh’s team may lead to effective IBS treatments. “DOP agonists could be a revolutionary new therapy for IBS, not only alleviating IBS-like symptoms but also providing benefits for stress and emotional regulation. Looking ahead, we aim to pursue clinical developments that expand the use of DOP agonists for IBS, in addition to treating depression,” Saitoh observes.
When compared to existing IBS treatments—including laxatives, antidiarrheals, pain relievers, and antispasmodics—addressing the underlying stress with DOP agonists may provide a more effective solution with fewer side effects. A better understanding of the roles of stress and brain chemistry in IBS development will be crucial for achieving this essential medical advancement. With encouraging possibilities on the horizon, future research will aim to apply Saitoh’s discoveries to human patients, offering significant relief to those suffering from IBS.
