KNT-127, A DELTA OPIOID RECEPTOR AGONIST, AMELIORATES PSYCHOLOGICAL STRESS-INDUCED IRRITABLE BOWEL SYNDROME-LIKE SYMPTOMS THROUGH THE CENTRAL NERVOUS SYSTEM
Authors: Yoshioka *Toshinori , Yamada Daisuke , Yamazaki Mayuna , Hamano Takumi , Kimiki Sayaka , Nagase Hiroshi , Saitoh Akiyoshi 
Published: February 2025

Abstract

Background & Objectives
Irritable bowel syndrome (IBS) is generally characterized by the symptoms of chronic abnormal intestinal movement and abdominal pain without organic pathological changes, and an increasing number of patients suffered from the symptoms. Notably, many IBS patients have concurrent psychiatric disorders, such as depression and anxiety. We then focused on a highly validated animal model of stress-induced psychiatric disorders, known as the chronic vicarious social defeat stress (cVSDS) model mice, which are repeatedly exposed to psychological stress alone, thereafter examining their intestinal conditions. While, the current mainstay of pharmacological therapeutic strategy for IBS is based on symptomatic treatments, so the radical treatment is required to be developed, such as drugs that target the central nervous system. We have proposed that delta opioid receptor (DOP) agonists are potential psychotropic drugs such as for depression. Thus, we also investigated whether a high selective DOP agonist, KNT-127, effects on the gastrointestinal symptoms in cVSDS mice.

Methods
cVSDS mice were produced with a 10-day exposure to witness of social defeat stress. Intestinal peristalsis was evaluated with the charcoal meal test (CMT), defecation frequency, and stool water content. Abdominal hyperalgesia was observed using capsaicin-induced hyperalgesia test (CHT). Intestinal pathological condition was assessed with histological states and intestinal permeability. The in vivo brain microdialysis study was performed to measure the regional extracellular glutamate concentrations. KNT- 127 was administrated 30 minutes before each test (10 mg/kg, subcutaneously; 30 nmol, intracerebroventricularly; 0.6 nmol, local infusion).

Results
cVSDS increased the intestinal transit ratio in the CMT, defecation frequency, and stool water content in mice. cVSDS mice also showed increased visceral pain-related behaviors in the CHT. These changes persisted over one month after the stress session. Whereas the pathological status and intestinal permeability of naive and cVSDS mice did not differ. Then, systematic and intracerebroventricular administration of KNT-127 alleviated the intestinal transport abnormality and relieved abdominal pain in cVSDS mice. It is noteworthy that microinfusion of KNT-127 in the insular cortex (IC), which is a part of the upper central nervous system controlling digestive functions and is involved in the process of coping with psychological stress, suppressed the cVSDS-induced increased intestinal peristalsis. Moreover, in vivo brain microdialysis study exhibited that a re-exposure of cVSDS raised the extracellular glutamate level in the IC, and it was restrained by administration of KNT-127.

Discussion & Conclusion
Our results indicate that cVSDS mice present IBS- like symptoms such as chronic intestinal peristaltic changes and abdominal hyperalgesia without organic lesions. Therefore, it should be considered the cVSDS paradigm as a novel animal model of IBS with high validity. Furthermore, we demonstrated that KNT-127, a selective DOP agonist, ameliorates cVSDS- induced IBS-like symptoms, and its underlying mechanism is involved in the modulation of the central nervous systems including the IC. We thus propose that the DOP is an attractive target for therapeutic drugs for IBS which has novel functional mechanisms entirely different from conventional drugs.