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

DiCello, Jesse J.; Carbone, Simona Elisa; Saito, Ayame; Pham, Vi; Szymaszkiewicz, Agata; Gondin, Arisbel B.; Alvi, Sadia; Marique, Kiliana; Shenoy, Priyank; Veldhuis, Nicholas A.; Fichna, Jakub; Canals, Meritxell; Christopoulos, Arthur; Valant, Celine; Poole, Daniel P.

Abstract

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.

Citation

DiCello, J. J., Carbone, S. E., Saito, A., Pham, V., Szymaszkiewicz, A., Gondin, A. B., Alvi, S., Marique, K., Shenoy, P., Veldhuis, N. A., Fichna, J., Canals, M., Christopoulos, A., Valant, C., & Poole, D. P. (2022). Positive allosteric modulation of endogenous delta opioid receptor signaling in the enteric nervous system is a potential treatment for gastrointestinal motility disorders. AJP - Gastrointestinal and Liver Physiology, 322(1), G66-G78. https://doi.org/10.1152/AJPGI.00297.2021

• Journal Article Type: Article
• Acceptance Date: Nov 2, 2021
• Online Publication Date: Nov 10, 2021
• Publication Date: Jan 1, 2022
• Deposit Date: Nov 19, 2021
• Publicly Available Date: Nov 11, 2022
• Journal: American Journal of Physiology - Gastrointestinal and Liver Physiology
• Print ISSN: 0193-1857
• Electronic ISSN: 1522-1547
• Publisher: American Physiological Society
• Peer Reviewed: Peer Reviewed
• Volume: 322
• Issue: 1
• Pages: G66-G78
• DOI: https://doi.org/10.1152/AJPGI.00297.2021
• Keywords: Physiology (medical); Gastroenterology; Hepatology; Physiology
• Public URL: https://nottingham-repository.worktribe.com/output/6738511
• Publisher URL: https://journals.physiology.org/doi/abs/10.1152/ajpgi.00297.2021