{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T02:48:47Z","timestamp":1788922127602,"version":"build-2803163510"},"reference-count":54,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T00:00:00Z","timestamp":1750982400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["235221301"],"award-info":[{"award-number":["235221301"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["390685689"],"award-info":[{"award-number":["390685689"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["01GQ2109B"],"award-info":[{"award-number":["01GQ2109B"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Berlin Mathematics Research Center MATH+","award":["235221301"],"award-info":[{"award-number":["235221301"]}]},{"name":"The Berlin Mathematics Research Center MATH+","award":["390685689"],"award-info":[{"award-number":["390685689"]}]},{"name":"The Berlin Mathematics Research Center MATH+","award":["01GQ2109B"],"award-info":[{"award-number":["01GQ2109B"]}]},{"DOI":"10.13039\/501100002347","name":"federal ministry of education and research","doi-asserted-by":"publisher","award":["235221301"],"award-info":[{"award-number":["235221301"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"federal ministry of education and research","doi-asserted-by":"publisher","award":["390685689"],"award-info":[{"award-number":["390685689"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"federal ministry of education and research","doi-asserted-by":"publisher","award":["01GQ2109B"],"award-info":[{"award-number":["01GQ2109B"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Endogenous opioids, such as Endomorphin-2, are not typically associated with severe constipation, unlike pharmaceutical opioids, which induce opioid-induced constipation (OIC) by activating \u03bc-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.<\/jats:p>","DOI":"10.3390\/ijms26136207","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T05:28:28Z","timestamp":1751347708000},"page":"6207","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Investigating Endogenous Opioids Unravels the Mechanisms Behind Opioid-Induced Constipation, a Mathematical Modeling Approach"],"prefix":"10.3390","volume":"26","author":[{"given":"Celvic","family":"Coomber","sequence":"first","affiliation":[{"name":"Institute of Mathematics, Technische Universit\u00e4t Berlin, 10623 Berlin, Germany"},{"name":"Zuse Institute Berlin, 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1428-349X","authenticated-orcid":false,"given":"Surahit","family":"Chewle","sequence":"additional","affiliation":[{"name":"Zuse Institute Berlin, 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7222-536X","authenticated-orcid":false,"given":"Christopher","family":"Secker","sequence":"additional","affiliation":[{"name":"Zuse Institute Berlin, 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantin","family":"Fackeldey","sequence":"additional","affiliation":[{"name":"Institute of Mathematics, Technische Universit\u00e4t Berlin, 10623 Berlin, Germany"},{"name":"Zuse Institute Berlin, 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Weber","sequence":"additional","affiliation":[{"name":"Zuse Institute Berlin, 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0114-7819","authenticated-orcid":false,"given":"Stefanie","family":"Winkelmann","sequence":"additional","affiliation":[{"name":"Zuse Institute Berlin, 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5232-2683","authenticated-orcid":false,"given":"Christof","family":"Sch\u00fctte","sequence":"additional","affiliation":[{"name":"Zuse Institute Berlin, 14195 Berlin, Germany"},{"name":"Department of Mathematics and Computer Science, Freie Universit\u00e4t Berlin, 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4940-8344","authenticated-orcid":false,"given":"Vikram","family":"Sunkara","sequence":"additional","affiliation":[{"name":"Zuse Institute Berlin, 14195 Berlin, Germany"},{"name":"Department of Mathematics and Computer Science, Freie Universit\u00e4t Berlin, 14195 Berlin, Germany"},{"name":"Deutsches Rheuma-Forschungszentrum, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kamato, D., Thach, L., Bernard, R., Chan, V., Zheng, W., Kaur, H., Brimble, M., Osman, N., and Little, P.J. 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