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Mu and Delta Opioid Receptors Are Coexpressed and Functionally Interact in the Enteric Nervous System of the Mouse Colon

BACKGROUND & AIMS: Functional interactions between the mu opioid receptor (MOR) and delta opioid receptor (DOR) represent a potential target for novel analgesics and may drive the effects of the clinically approved drug eluxadoline for the treatment of diarrhea-predominant irritable bowel syndro...

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Autores principales: DiCello, Jesse J., Carbone, Simona E., Saito, Ayame, Rajasekhar, Pradeep, Ceredig, Rhian A., Pham, Vi, Valant, Celine, Christopoulos, Arthur, Veldhuis, Nicholas A., Canals, Meritxell, Massotte, Dominique, Poole, Daniel P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036548/
https://www.ncbi.nlm.nih.gov/pubmed/31759144
http://dx.doi.org/10.1016/j.jcmgh.2019.11.006
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author DiCello, Jesse J.
Carbone, Simona E.
Saito, Ayame
Rajasekhar, Pradeep
Ceredig, Rhian A.
Pham, Vi
Valant, Celine
Christopoulos, Arthur
Veldhuis, Nicholas A.
Canals, Meritxell
Massotte, Dominique
Poole, Daniel P.
author_facet DiCello, Jesse J.
Carbone, Simona E.
Saito, Ayame
Rajasekhar, Pradeep
Ceredig, Rhian A.
Pham, Vi
Valant, Celine
Christopoulos, Arthur
Veldhuis, Nicholas A.
Canals, Meritxell
Massotte, Dominique
Poole, Daniel P.
author_sort DiCello, Jesse J.
collection PubMed
description BACKGROUND & AIMS: Functional interactions between the mu opioid receptor (MOR) and delta opioid receptor (DOR) represent a potential target for novel analgesics and may drive the effects of the clinically approved drug eluxadoline for the treatment of diarrhea-predominant irritable bowel syndrome. Although the enteric nervous system (ENS) is a likely site of action, the coexpression and potential interaction between MOR and DOR in the ENS are largely undefined. In the present study, we have characterized the distribution of MOR in the mouse ENS and examined MOR-DOR interactions by using pharmacologic and cell biology techniques. METHODS: MOR and DOR expression was defined by using MORmCherry and MORmCherry–DOR-eGFP knockin mice. MOR-DOR interactions were assessed by using DOR-eGFP internalization assays and by pharmacologic analysis of neurogenic contractions of the colon. RESULTS: Although MOR was expressed by approximately half of all myenteric neurons, MOR-positive submucosal neurons were rarely observed. There was extensive overlap between MOR and DOR in both excitatory and inhibitory pathways involved in the coordination of intestinal motility. MOR and DOR can functionally interact, as shown through heterologous desensitization of MOR-dependent responses by DOR agonists. Functional evidence suggests that MOR and DOR may not exist as heteromers in the ENS. Pharmacologic studies show no evidence of cooperativity between MOR and DOR. DOR internalizes independently of MOR in myenteric neurons, and MOR-evoked contractions are unaffected by the sequestration of DOR. CONCLUSIONS: Collectively, these findings demonstrate that although MOR and DOR are coexpressed in the ENS and functionally interact, they are unlikely to exist as heteromers under physiological conditions.
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spelling pubmed-70365482020-03-02 Mu and Delta Opioid Receptors Are Coexpressed and Functionally Interact in the Enteric Nervous System of the Mouse Colon DiCello, Jesse J. Carbone, Simona E. Saito, Ayame Rajasekhar, Pradeep Ceredig, Rhian A. Pham, Vi Valant, Celine Christopoulos, Arthur Veldhuis, Nicholas A. Canals, Meritxell Massotte, Dominique Poole, Daniel P. Cell Mol Gastroenterol Hepatol Original Research BACKGROUND & AIMS: Functional interactions between the mu opioid receptor (MOR) and delta opioid receptor (DOR) represent a potential target for novel analgesics and may drive the effects of the clinically approved drug eluxadoline for the treatment of diarrhea-predominant irritable bowel syndrome. Although the enteric nervous system (ENS) is a likely site of action, the coexpression and potential interaction between MOR and DOR in the ENS are largely undefined. In the present study, we have characterized the distribution of MOR in the mouse ENS and examined MOR-DOR interactions by using pharmacologic and cell biology techniques. METHODS: MOR and DOR expression was defined by using MORmCherry and MORmCherry–DOR-eGFP knockin mice. MOR-DOR interactions were assessed by using DOR-eGFP internalization assays and by pharmacologic analysis of neurogenic contractions of the colon. RESULTS: Although MOR was expressed by approximately half of all myenteric neurons, MOR-positive submucosal neurons were rarely observed. There was extensive overlap between MOR and DOR in both excitatory and inhibitory pathways involved in the coordination of intestinal motility. MOR and DOR can functionally interact, as shown through heterologous desensitization of MOR-dependent responses by DOR agonists. Functional evidence suggests that MOR and DOR may not exist as heteromers in the ENS. Pharmacologic studies show no evidence of cooperativity between MOR and DOR. DOR internalizes independently of MOR in myenteric neurons, and MOR-evoked contractions are unaffected by the sequestration of DOR. CONCLUSIONS: Collectively, these findings demonstrate that although MOR and DOR are coexpressed in the ENS and functionally interact, they are unlikely to exist as heteromers under physiological conditions. Elsevier 2019-11-20 /pmc/articles/PMC7036548/ /pubmed/31759144 http://dx.doi.org/10.1016/j.jcmgh.2019.11.006 Text en © 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Research
DiCello, Jesse J.
Carbone, Simona E.
Saito, Ayame
Rajasekhar, Pradeep
Ceredig, Rhian A.
Pham, Vi
Valant, Celine
Christopoulos, Arthur
Veldhuis, Nicholas A.
Canals, Meritxell
Massotte, Dominique
Poole, Daniel P.
Mu and Delta Opioid Receptors Are Coexpressed and Functionally Interact in the Enteric Nervous System of the Mouse Colon
title Mu and Delta Opioid Receptors Are Coexpressed and Functionally Interact in the Enteric Nervous System of the Mouse Colon
title_full Mu and Delta Opioid Receptors Are Coexpressed and Functionally Interact in the Enteric Nervous System of the Mouse Colon
title_fullStr Mu and Delta Opioid Receptors Are Coexpressed and Functionally Interact in the Enteric Nervous System of the Mouse Colon
title_full_unstemmed Mu and Delta Opioid Receptors Are Coexpressed and Functionally Interact in the Enteric Nervous System of the Mouse Colon
title_short Mu and Delta Opioid Receptors Are Coexpressed and Functionally Interact in the Enteric Nervous System of the Mouse Colon
title_sort mu and delta opioid receptors are coexpressed and functionally interact in the enteric nervous system of the mouse colon
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036548/
https://www.ncbi.nlm.nih.gov/pubmed/31759144
http://dx.doi.org/10.1016/j.jcmgh.2019.11.006
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