New research suggests that δ-receptor agonists regulate intestinal motility and relieve abdominal pain in a mouse model of irritable bowel syndrome, potentially offering a novel CNS-targeted treatment approach.
Study: Agonists of the opioid δ-receptor improve irritable bowel syndrome-like symptoms via the central nervous system. Image Credit: Orawan Pattarawimonchai/Shutterstock.com
In a recent study published in the British Journal of Pharmacology, a group of researchers evaluated the effects of opioid delta-receptor agonists on Irritable bowel syndrome (IBS)-like symptoms in a chronic vicarious social defeat stress mouse model.
Background
IBS affects over 10% of the global population, causing significant discomfort, reduced quality of life, and an economic burden exceeding billions annually. It is characterized by altered bowel habits, abdominal pain, and gut-brain axis dysregulation.
Current treatments primarily focus on symptom management rather than addressing underlying neurobiological mechanisms. While stress is a well-established trigger for IBS, the role of the central nervous system in modulating gut function remains underexplored.
Opioid delta-receptor agonists have demonstrated potential in treating stress-related disorders, with recent research highlighting their role in gut-brain axis regulation and mood stabilization. However, their specific effects on IBS-like symptoms remain largely unexplored.
Exploring novel neuromodulatory interventions could lead to more effective therapeutic strategies. Further research is needed to confirm the mechanistic role of opioid delta-receptor agonists in gut-brain axis modulation.
About the study
Animal care and experimental procedures were conducted following ethical guidelines. Male C57BL/6J mice, aged 4-5 weeks, were housed under controlled environmental conditions.
Chronic vicarious social defeat stress (cVSDS) was induced by exposing test mice to aggressive Institute of Cancer Research (ICR) retired breeder mice for 10 consecutive days. Mice were then assessed for IBS-like symptoms.
Intestinal motility was measured using the Charcoal Meal Test, where mice underwent a 14-16 hour fasting period before receiving a standardized ink solution. The distance traveled by the ink within the intestines was quantified.
Capsaicin-Induced Hyperalgesia Test evaluated visceral pain responses by injecting capsaicin intra-rectally and recording pain-related behaviors.
To assess the central role of opioid delta-receptor agonists, Kyushu-Nagase-Tokyo-127 (KNT-127), a selective agonist, was administered systemically and intracerebroventricularly.
Additionally, a subgroup received naltrindole, a delta-opioid receptor antagonist, to determine receptor-specific effects. In vivo brain microdialysis was performed to analyze extracellular glutamate concentrations in the insular cortex.
Statistical analyses were conducted using Analysis of Variance (ANOVA) followed by post hoc tests. Sample sizes were determined using power analysis, and investigators were blinded to group assignments.
Study results
Systemic administration of KNT-127 significantly reduced intestinal hypermotility in cVSDS mice compared to controls. The charcoal transit ratio, a measure of gastrointestinal motility, was elevated in cVSDS mice but normalized following KNT-127 administration. This effect was absent in naive mice, indicating the compound’s selective action on stress-induced intestinal dysfunction.
In the Capsaicin-Induced Hyperalgesia Test, cVSDS mice exhibited increased pain-related behaviors, including squashing and jumping. KNT-127 administration reduced these behaviors, suggesting a potential analgesic effect. Notably, licking behavior, indicative of mild discomfort, remained unchanged, indicating specificity in targeting severe visceral pain.
Further analysis showed that intracerebroventricular administration of KNT-127 replicated the systemic effects, suggesting central nervous system involvement. Conversely, administration of naltrindole reversed the beneficial effects of KNT-127, confirming that opioid delta-receptor activation mediated symptom relief.
This provided strong evidence that the therapeutic effects of KNT-127 were centrally driven rather than due to direct peripheral action.
To explore the underlying mechanism, in vivo brain microdialysis was performed to assess extracellular glutamate levels in the insular cortex, a key region associated with visceral pain and stress regulation.
Results showed that cVSDS mice had significantly elevated glutamate levels compared to controls, indicating heightened excitatory neurotransmission. KNT-127 administration effectively normalized these glutamate levels, reinforcing its neuromodulatory action.
To further confirm the role of the insular cortex in mediating these effects, a microinfusion of KNT-127 directly into this brain region was performed. The localized administration significantly improved intestinal motility, further supporting the hypothesis that opioid delta-receptor activation within the insular cortex plays a pivotal role in IBS-like symptom modulation.
This highlights a crucial central component in the gut-brain axis, differentiating this approach from traditional IBS treatments that primarily target peripheral mechanisms.
These findings suggest that opioid delta-receptor activation modulates both peripheral and central components of IBS-like symptoms. Unlike conventional IBS treatments, which mainly focus on peripheral pathways, KNT-127 exhibits a dual mechanism by influencing gut function and stress-related neural circuits.
This broader action positions it as a potentially transformative therapeutic candidate for IBS treatment, addressing both the neurological and gastrointestinal aspects of the disorder.
Conclusions
To summarize, the study highlights the potential of opioid delta-receptor agonists as a novel treatment approach for IBS. By modulating glutamatergic activity in the insular cortex, KNT-127 effectively alleviates stress-induced intestinal hypermotility and visceral pain.
These findings indicate a breakthrough in IBS treatment, suggesting that targeting opioid delta-receptors can provide relief by modulating both the gut and the brain. This approach may revolutionize IBS management by addressing both symptom severity and underlying neurological dysfunction.
