Opioid-Induced Constipation: Mechanistic Insights, Experimental Models, and Future Perspectives.

Area of Science:

• Gastroenterology
• Pharmacology
• Neuroscience

Background:

• Opioid-induced constipation (OIC) affects 60-90% of patients on opioid analgesics, significantly impacting quality of life.
• OIC pathogenesis involves peripheral μ-opioid receptor (MOR) activation, leading to suppressed gut motility and function.
• Central mechanisms via the brain-gut axis, gut barrier disruption, and microbiota dysbiosis also contribute to OIC.

Purpose of the Study:

• To review the multifactorial pathogenesis of opioid-induced constipation.
• To highlight the limitations of current animal models in OIC research.
• To propose future research directions for precise OIC management.

Main Methods:

• Literature review of OIC pathogenesis.
• Analysis of mechanisms involving peripheral and central opioid receptor activation.
• Evaluation of the role of gut barrier, microbiota, and neuroinflammation.

Main Results:

• Peripheral MOR activation in the colon, with limited tolerance development, is a primary driver of OIC.
• Enteric glial cells, interstitial cells of Cajal, and brain-gut axis interactions are implicated.
• Opioid-induced gut barrier disruption, dysbiosis, and inflammation form a self-reinforcing cycle.

Conclusions:

• OIC is a complex condition with interconnected peripheral, central, and microbial factors.
• Current animal models have limitations in translational validity for OIC.
• Future research should focus on standardized models and mechanism-based therapies like peripherally acting MOR antagonists and microbiota interventions.