TY - JOUR A1 - Coomber, Celvic A1 - Chewle, Surahit A1 - Secker, Christopher A1 - Fackeldey, Konstantin A1 - Weber, Marcus A1 - Winkelmann, Stefanie A1 - Schütte, Christof A1 - Sunkara, Vikram T1 - Investigating Endogenous Opioids Unravels the Mechanisms Behind Opioid-Induced Constipation, a Mathematical Modeling Approach JF - International Journal of Molecular Sciences N2 - 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. Y1 - 2025 U6 - https://doi.org/10.3390/ijms26136207 VL - 26 IS - 13 ER -