Sa1738 – Olorinab (Formerly Apd371), a Peripherally Restricted, Highly Selective, Full Agonist of the Cannabinoid Receptor 2 (CB2), Reduces Visceral Hypersensitivity in Animal Models

Abstract

Objective: Abdominal pain is a key symptom of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). IBD, which includes colitis, is characterized by periods of acute inflammation and remission, whereas IBS is defined by altered bowel habits and abdominal pain without overt inflammation. Therapies exist to treat gut inflammation in IBD and motility dysfunction in IBS, but abdominal pain remains a significant unmet need in both disorders. We tested whether olorinab, a highly selective, full agonist of CB2, reduced visceral hypersensitivity in an IBD-like rat model of colitis and an IBS-like mouse model of chronic visceral hypersensitivity (CVH). Method(s): Colitis was induced in male 6- to 7-week-old Sprague Dawley rats by 1 rectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) 12 mg in 35% ethanol. Control or colitis (4 days after TNBS) rats were orally administered either vehicle (0.5% methylcellulose) or olorinab 3 or 30 mg/kg twice daily (BID) by oral gavage for 5 days, starting 1 day before TNBS administration. CVH was evaluated in a mouse model after complete resolution of acute TNBS-induced inflammation. Control or CVH mice were orally administered vehicle or olorinab 3, 10, or 30 mg/kg BID on days 24 to 28 after TNBS administration. Visceral mechanosensitivity was assessed in vivo by quantifying visceromotor responses (VMR) to colorectal distension (CRD; 0-80 mm Hg). Generalized estimating equations (SPSS software) were used for analysis with P<0.05 considered significant. Result(s): TNBS-treated rats displayed significant colonic inflammation and increased myeloperoxidase activity compared with controls (P<0.01, N=9/group). Vehicle- treated colitis rats displayed visceral hypersensitivity, with significantly elevated VMR to CRD at distension pressures of 20 mm Hg (P<0.05) and 40-80 mm Hg (P<0.01; N=9/group). Olorinab-treated colitis rats had significantly reduced VMR to CRD compared with vehicle-treated colitis rats (P<0.001, N=9/group). In contrast, control rats treated with olorinab did not show altered visceral sensitivity to CRD (P>0.05, N=8-11/group). Vehicle-treated CVH mice exhibited hypersensitivity compared with healthy mice (N=14/group), with significantly elevated VMR to CRD at distension pressures of 40, 50, and 60 mm Hg (P<0.05, <0.01, and <0.0001). Olorinab-treated CVH mice (N=10-12/group) had significantly reduced VMR to CRD compared with vehicle-treated CVH mice (N=14). Conclusion(s): Olorinab reduced visceral hypersensitivity in animal models of IBD and IBS, suggesting that activation of CB2 causes antinociceptive actions in visceral sensory pathways. Olorinab, through its selectivity, is designed to provide pain relief without psychotropic effects and without the potential for dependence. Therefore, olorinab may provide a novel therapy for IBD- and IBS-associated abdominal pain.Copyright © 2019 AGA Institute. All rights reserved.