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Targeting the endocannabinoid system for the treatment of abdominal pain in irritable bowel syndrome

Abstract

The management of visceral pain in patients with disorders of gut–brain interaction, notably irritable bowel syndrome, presents a considerable clinical challenge, with few available treatment options. Patients are increasingly using cannabis and cannabinoids to control abdominal pain. Cannabis acts on receptors of the endocannabinoid system, an endogenous system of lipid mediators that regulates gastrointestinal function and pain processing pathways in health and disease. The endocannabinoid system represents a logical molecular therapeutic target for the treatment of pain in irritable bowel syndrome. Here, we review the physiological and pathophysiological functions of the endocannabinoid system with a focus on the peripheral and central regulation of gastrointestinal function and visceral nociception. We address the use of cannabinoids in pain management, comparing them to other treatment modalities, including opioids and neuromodulators. Finally, we discuss emerging therapeutic candidates targeting the endocannabinoid system for the treatment of pain in irritable bowel syndrome.

Key points

  • The management of abdominal pain in disorders of gut–brain interaction, including irritable bowel syndrome (IBS), is challenging.

  • Patients are increasingly using cannabis and cannabinoids as an alternative therapy to treat pain and altered bowel habits in IBS.

  • Cannabis acts on the cannabinoid receptors (CB1 and CB2) of the endocannabinoid system (ECS), which consists of ligands for these receptors, anandamide and 2-arachidonoylglycerol as well as the biosynthetic and degradative enzymes for these ligands.

  • The ECS is a logical molecular target for the treatment of IBS as it regulates gastrointestinal motility, secretion, barrier function, inflammation, gut microbiota and visceral sensitivity.

  • Cannabinoid therapeutics have been developed but are of limited use in managing pain in IBS; the effects of cannabis have not been rigorously examined in much-needed large clinical trials.

  • Evidence supports the putative analgesic properties of a peripherally restricted CB2 receptor agonist in IBS. Future therapies could target additional ECS components for the treatment of IBS and other disorders of gut–brain interaction.

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Fig. 1: CB1 and CB2 expression in cell types throughout the gut–brain–microbiota axis.
Fig. 2: CB1 and CB2 structure, second messenger signalling mechanisms, and downstream targets within cells.
Fig. 3: Endocannabinoid system targets of visceral pain.
Fig. 4: Actions of the endocannabinoid system as they relate to the gastrointestinal tract, motility, gut microbiota, immune function and visceral pain.
Fig. 5: Potential therapeutic intervention strategies to modulate the function of CB1 and CB2.

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Acknowledgements

The authors are grateful to the National Health and Medical Research Council of Australia (Investigator Leadership Grant, APP2008727, and Development Grant APP2014250 to S.M.B.), the Australian Research Council (Discovery Project, DP180101395 to S.M.B.), Department of Veterans Affairs Senior Research Career Scientist Award (BX003610 to B.V.G.M.), Department of Veterans Affairs (Merit Grant BX002188 to B.G.V.M.), National Institutes of Health (1U01 NS113869 and 1U01NS113871 to S.M.B.; R01 NIDDK119125-01A1 to B.V.G.M.), Oklahoma Center for the Advancement of Science (HR-18-040 to B.V.G.M.), Canadian Institutes of Health Research (FDN148380 to K.A.S.), the University of Leuven (Methusalem Grant to J.T.) and the Fund for Scientific Research Flanders (Research Grants to J.T.) for support of the original research performed in the authors’ laboratories.

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S.M.B. has provided scientific advice and received research grant support from AusHealth, Arena Pharmaceuticals, Ironwood Pharmaceuticals, Takeda Pharmaceuticals, and Sosie Heptares. B.V.G.M. has provided scientific advice and assistance to Nocion Therapeutics Inc., Teva Branded Pharmaceuticals Products R & D, Bayer Healthcare, Ironwood Pharmaceuticals, EA Pharma Co. Ltd and Blue Therapeutics. G.S. has provided scientific advice and assistance to Nextbiomics and has served on a Speaker bureau for AlfaSigma, Takeda, Farmagens and Interalia Pharmaceuticals. K.A.S. has provided scientific advice and assistance to Arena Pharmaceuticals and GW Pharmaceuticals and has served on a speaker bureau for Abbvie and received research support from Abalone Inc. M.S. has provided scientific advice and assistance to CaraCare, Bayer AG, Dr. Schwabe, Echo-Pharma, and Medice and has served on a Speaker bureau for Falkfoundation, Microbiotica, Bayer AG, Dr. Schwabe, Medice, Kyowa Kirin, Hexal, and HlH Biopharma. J.T. has provided scientific advice and assistance to Adare, AlfaSigma, Arena, Bayer, Christian Hansen, Clasado, Danone, Devintec, Falk, Grünenthal, Ironwood, Janssen, Kiowa Kirin, Menarini, Mylan, Neurogastrx, Neutec, Novartis, Nutricia, Ricordati Shionogi, Takeda, Truvion, Tsumura, Zealand, and Zeria pharmaceuticals, has served on a Speaker bureau for Abbott, Allergan, AstraZeneca, Janssen, Kiowa Kirin, Menarini, Mylan, Novartis, Shire, Takeda, Wellspect and Zeria, and has received research support from Biohit, Kiowa Kirin, Shire, Sofar and Takeda Pharmaceuticals.

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Nature Reviews Gastroenterology & Hepatology thanks Emeran Mayer, Ravi Bhatt, Raquel Abalo and the other anonymous reviewer for their contribution to the peer review of this work.

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Brierley, S.M., Greenwood-Van Meerveld, B., Sarnelli, G. et al. Targeting the endocannabinoid system for the treatment of abdominal pain in irritable bowel syndrome. Nat Rev Gastroenterol Hepatol (2022). https://doi.org/10.1038/s41575-022-00682-y

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