# Investigating Endogenous Opioids Unravels the Mechanisms Behind Opioid-Induced Constipation, a Mathematical Modeling Approach

## TL;DR

This study uses a mathematical model to explore how opioid drugs cause constipation, finding that differences in how opioids break down could lead to new treatments.

## Contribution

The novelty lies in using a mathematical model to show that opioid degradation rates, not serotonin signaling, are key to opioid-induced constipation.

## Key findings

- Opioids affect adenylyl cyclase activity but not serotonin signaling in the gut.
- Endogenous opioids like Endomorphin-2 differ from pharmaceutical opioids in degradation rates, impacting cAMP recovery.
- Modulating opioid degradation rates in the gut could mitigate opioid-induced constipation.

## Abstract

Endogenous opioids, such as Endomorphin-2, are not typically associated with severe constipation, unlike pharmaceutical opioids, which induce opioid-induced constipation (OIC) by activating μ-opioid receptors in the gastrointestinal tract. In this study, we present a mathematical model, which integrates the serotonergic and opioid pathways, simulating the interaction between serotonin and opioid signaling within the enteric nervous system (ENS). The model explores the mechanisms underlying OIC, with a focus on the change in adenylyl cyclase (AC) activity, cAMP accumulation, and the distinct functionalities of Endomorphin-2 compared to commonly used pharmaceutical opioids. We study the effects of Morphine, Fentanyl, and Methadone and contrast them with Endomorphin-2. Our findings reveal that opioids do not perturb the signaling of serotonin, but only the activity of AC, suggesting that serotonin levels have no influence on improving opioid-induced constipation. Furthermore, this study reveals that the primary difference between endogenous and pharmaceutical opioids is their degradation rates. This finding shows that modulating opioid degradation rates significantly improves cAMP recovery. In conclusion, our insights steer towards exploring opioid degrading enzymes, localized to the gut, as a strategy for mitigating OIC.