Positive allosteric modulation of endogenous delta opioid receptor signaling in the enteric nervous system is a potential treatment for gastrointestinal motility disorders.

Autor:	DiCello JJ; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.; Department of Physiology, Monash University Biomedicine Discovery Institute, Clayton, Victoria, Australia.; Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Parkville, Victoria, Australia., Carbone SE; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.; Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Parkville, Victoria, Australia., Saito A; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia., Pham V; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia., Szymaszkiewicz A; Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland., Gondin AB; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.; Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Parkville, Victoria, Australia., Alvi S; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia., Marique K; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia., Shenoy P; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.; Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Parkville, Victoria, Australia., Veldhuis NA; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.; Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Parkville, Victoria, Australia., Fichna J; Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland., Canals M; Division of Physiology, Pharmacology and Neuroscience, Queen's Medical Centre, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom.; Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, United Kingdom., Christopoulos A; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia., Valant C; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia., Poole DP; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.; Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Parkville, Victoria, Australia.
Jazyk:	angličtina
Zdroj:	American journal of physiology. Gastrointestinal and liver physiology [Am J Physiol Gastrointest Liver Physiol] 2022 Jan 01; Vol. 322 (1), pp. G66-G78. Date of Electronic Publication: 2021 Nov 10.
DOI:	10.1152/ajpgi.00297.2021
Abstrakt:	Allosteric modulators (AMs) are molecules that can fine-tune signaling by G protein-coupled receptors (GPCRs). Although they are a promising therapeutic approach for treating a range of disorders, allosteric modulation of GPCRs in the context of the enteric nervous system (ENS) and digestive dysfunction remains largely unexplored. This study examined allosteric modulation of the delta opioid receptor (DOR) in the ENS and assessed the suitability of DOR AMs for the treatment of irritable bowel syndrome (IBS) symptoms using mouse models. The effects of the positive allosteric modulator (PAM) of DOR, BMS-986187, on neurogenic contractions of the mouse colon and on DOR internalization in enteric neurons were quantified. The ability of BMS-986187 to influence colonic motility was assessed both in vitro and in vivo. BMS-986187 displayed DOR-selective PAM-agonist activity and orthosteric agonist probe dependence in the mouse colon. BMS-986187 augmented the inhibitory effects of DOR agonists on neurogenic contractions and enhanced reflex-evoked DOR internalization in myenteric neurons. BMS-986187 significantly increased DOR endocytosis in myenteric neurons in response to the weakly internalizing agonist ARM390. BMS-986187 reduced the generation of complex motor patterns in the isolated intact colon. BMS-986187 reduced fecal output and diarrhea onset in the novel environment stress and castor oil models of IBS symptoms, respectively. DOR PAMs enhance DOR-mediated signaling in the ENS and have potential benefit for the treatment of dysmotility. This study provides proof of concept to support the use of GPCR AMs for the treatment of gastrointestinal motility disorders. NEW & NOTEWORTHY This study assesses the use of positive allosteric modulation as a pharmacological approach to enhance opioid receptor signaling in the enteric nervous system. We demonstrate that selective modulation of endogenous delta opioid receptor signaling can suppress colonic motility without causing constipation. We propose that allosteric modulation of opioid receptor signaling may be a therapeutic strategy to normalize gastrointestinal motility in conditions such as irritable bowel syndrome.
Databáze:	MEDLINE
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