Olorinab (APD371), a peripherally acting, highly selective, full agonist of the cannabinoid receptor 2, reduces colitis-induced acute and chronic visceral hypersensitivity in rodents
Joel Castro, Sonia Garcia-Caraballo, Jessica Maddern, Gudrun Schober, Amanda Lumsden, Andrea Harrington, Shirdi Schmiel, Beatriz Lindstrom, John Adams, Stuart M Brierley, Joel Castro, Sonia Garcia-Caraballo, Jessica Maddern, Gudrun Schober, Amanda Lumsden, Andrea Harrington, Shirdi Schmiel, Beatriz Lindstrom, John Adams, Stuart M Brierley
Abstract
Abdominal pain is a key symptom of inflammatory bowel disease and irritable bowel syndrome, for which there are inadequate therapeutic options. We tested whether olorinab-a highly selective, full agonist of the cannabinoid receptor 2 (CB2)-reduced visceral hypersensitivity in models of colitis and chronic visceral hypersensitivity (CVH). In rodents, colitis was induced by intrarectal administration of nitrobenzene sulfonic acid derivatives. Control or colitis animals were administered vehicle or olorinab (3 or 30 mg/kg) twice daily by oral gavage for 5 days, starting 1 day before colitis induction. Chronic visceral hypersensitivity mice were administered olorinab (1, 3, 10, or 30 mg/kg) twice daily by oral gavage for 5 days, starting 24 days after colitis induction. Visceral mechanosensitivity was assessed in vivo by quantifying visceromotor responses (VMRs) to colorectal distension. Ex vivo afferent recordings determined colonic nociceptor firing evoked by mechanical stimuli. Colitis and CVH animals displayed significantly elevated VMRs to colorectal distension and colonic nociceptor hypersensitivity. Olorinab treatment significantly reduced VMRs to control levels in colitis and CVH animals. In addition, olorinab reduced nociceptor hypersensitivity in colitis and CVH states in a concentration- and CB2-dependent manner. By contrast, olorinab did not alter VMRs nor nociceptor responsiveness in control animals. Cannabinoid receptor 2 mRNA was detected in colonic tissue, particularly within epithelial cells, and dorsal root ganglia, with no significant differences between healthy, colitis, and CVH states. These results demonstrate that olorinab reduces visceral hypersensitivity through CB2 agonism in animal models, suggesting that olorinab may provide a novel therapy for inflammatory bowel disease- and irritable bowel syndrome-associated abdominal pain.
Trial registration: ClinicalTrials.gov NCT03155945.
Conflict of interest statement
S. Schmiel, B. Lindstrom, and J. Adams are employees of Arena Pharmaceuticals, Inc. S.M. Brierley received research funding from Arena Pharmaceuticals to conduct the study. The remaining authors have no conflicts of interest to declare. Data from this study were previously presented in part at Digestive Disease Week (DDW) on May 2, 2020, as a virtual ePoster; DDW 2019 on May 18 to 21, 2019, in San Diego, CA; American Neurogastroenterology and Motility Society (ANMS) Annual Meeting on August 16 to 18, 2019, in Chicago, IL; United European Gastroenterology (UEG) Week on October 11, 2020, as a virtual presentation; and UEGW on October 19 to 23, 2019, in Barcelona, Spain.
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.
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