Targeting the Brain: A New Path Forward for IBS Treatment

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According to a new study, opioid delta-receptor agonists (DOP) may help alleviate symptoms of irritable bowel syndrome (IBS) by targeting the central nervous system rather than the intestines directly. Investigators cited the growing evidence closely linking IBS and psychological stress as one of the main motivations for this study.^1,2

IBS—which causes symptoms such as abdominal pain, bloating, gas, and changes in bowel movements, including diarrhea or constipation—affects approximately 10% of the global population. Furthermore, approximately 33% of individuals with IBS also experience anxiety or depression.³ However, the underlying causes and mechanisms of IBS remain unclear. As a result, treatments for IBS focus on managing symptoms rather than addressing the root cause of the disorder. Professor Akiyoshi Saitoh, PhD, from the Tokyo University of Science (TUS) in Japan and his research group have spent the past 10 years exploring this issue.

Saitoh et al aimed to address the connection between IBS and stress by exploring a novel animal model. In a 2022 study, they developed a model in which mice who were repeatedly exposed to psychological stress developed symptoms similar to IBS-D, including overly active intestines and heightened sensitivity to abdominal pain, despite no physical damage to their organs. The investigators utilized a method called chronic vicarious social defeat stress (cVSDS). In the cVSDS animal model, the subject mouse repeatedly witnesses a territorial, aggressive mouse defeating a cage mate, which induces indirect chronic stress. The investigators then sought to determine whether DOP in the brain could serve as promising drug targets for treating stress-induced IBS by performing a series of experiments to observe the effects of DOP agonists on IBS symptoms and chemical signaling in the brain. For example, investigators measured the speed of a charcoal meal through mice subjects’ intestines to assess gastrointestinal motility and evaluate the impact of stress or treatments on bowel movement speed. They directly measured neurotransmitter concentrations using in vivo brain microdialysis, which revealed that reexposure to VSDS increased glutamate levels in the insular cortex, but elevated levels were normalized with DOP agonists.

This suggests that the administration of DOP agonists may help relieve abdominal pain and regulate bowel movements in cVSDS mice. Applying the DOP agonists directly to the insular cortex had similar effects on IBS symptoms as systemic treatment.

“Our findings demonstrated that DOP agonists acted directly on the central nervous system to improve diarrhea-predominant IBS symptoms in mice, and suggest that the mechanism of action involves the regulation of glutamate neurotransmission in the insular cortex,” said Saitoh.

This continued research by Saitoh et al could illuminate a new path forward for effective IBS treatments. Compared with currently available IBS treatments, Targeting the underlying stress with DOP agonists may offer a more definitive solution with minimal adverse effects. Further research is needed on the relationship between stress and IBS, but the investigators hope that future studies will translate Saitoh et al’s findings to humans, bringing relief to the many individuals affected by IBS.

“DOP agonists could represent a groundbreaking new IBS treatment that not only improves IBS-like symptoms but also provides anti-stress and emotional regulation effects. In the future, we would like to conduct clinical developments with the goal of expanding the indication of DOP agonists for IBS, in addition to depression,” said Saitoh.

The study was published online in the British Journal of Pharmacology.¹

References

1. Yoshioka T, Kimiki S, Yamazaki M, et al. Agonists of the opioid δ-receptor improve irritable bowel syndrome-like symptoms via the central nervous system. Br J Pharmacol. 2024 Dec 25. Online ahead of print.

2. Beyond the gut: a new frontier in IBS treatment by targeting the brain. Tokyo University of Science. News release. February 5, 2025. https://www.tus.ac.jp/en/mediarelations/archive/20250205_8762.html

3. Staudacher HM, Black CJ, Teasdale SB, et al. Irritable bowel syndrome and mental health comorbidity — approach to multidisciplinary management. Nat Rev Gastroenterol Hepatol. 2023;20(9):582-596.