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

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.