Agonists of the opioid δ‐receptor improve irritable bowel syndrome‐like symptoms via the central nervous system

Abstract Background and Purpose Irritable bowel syndrome (IBS) is a common condition that is challenging to treat, and novel drugs are needed for this condition. Previously, a chronic vicarious social defeat stress (cVSDS) mouse model exhibits IBS‐like symptoms. Also agonists of the opioid δ‐receptor exert anti‐stress effects in rodents with minimal adverse effects. Here, we evaluated the effects of δ‐receptor agonists on the IBS‐like symptoms in cVSDS mice. Experimental Approach cVSDS mice (male C57BL/6J mice) were prepared following a 10‐day exposure to witness of social defeat stress. Subsequently, intestinal peristaltic motility and abdominal hyperalgesia were evaluated using the charcoal meal test (CMT) and capsaicin‐induced hyperalgesia test (CHT), respectively. Extracellular glutamate levels were measured using in vivo brain microdialysis. The drug was singly administrated 30 min before testing. Key Results In cVSDS mice, systemic (10 mg kg −1 ) and intracerebroventricular (30 nmol) administration of a δ‐receptor agonist regulated intestinal peristalsis in the CMT and relieved abdominal pain in the CHT. Effects of systemic administration were blocked by intracerebroventricular injection of a δ‐receptor inhibitor. Local infusion of the δ‐receptor agonist (0.6 nmol) into the insular cortex improved cVSDS‐induced intestinal hypermotility. The in vivo brain microdialysis study showed that re‐exposure to VSDS elevated the extracellular glutamate levels in the IC, which was restored by the δ‐receptor agonist. Conclusions and Implications We propose that agonists of opioid δ‐receptors are potential drugs for the radical treatment of IBS because they can ameliorate IBS‐like symptoms via the CNS, specifically the insular cortex.