Olorinab (APD371), a peripherally restricted, highly selective, full agonist of the cannabinoid receptor 2 (CB2), reduces colitis-induced visceral hypersensitivity in rats

Objective : Inflammatory bowel disease (IBD), which includes patients with Crohn ' s disease and ulcerative colitis, is a chronic relapsing disorder affecting the gastrointestinal tract. Abdominal pain is a key symptom of IBD patients, yet a large unmet need for novel therapeutics exists, as many patients do not respond to clinically approved drugs, including TNF and integrin blockers (Neurath MF. Nat Rev Gastroenterol Hepatol. 2017;14:269- 278). We aimed to determine if APD371, a highly selective, full agonist of the CB2 receptor, reduces colitis- induced visceral hypersensitivity in rats. Methods : Male 6- to 7- week- old Sprague Dawley rats were given individual identification numbers and randomly allocated to treatment groups. Colitis was induced by a single rectal administration of 2,4,6- trinitrobenzene sulfonic acid (TNBS) 12 mg in 35% ethanol. Control or colitis (4 days post- TNBS treatment) rats were orally administered either vehicle (0.5% methylcellulose) or the CB2 agonist APD371 (30 mg/kg) twice daily by oral gavage for 5 days, commencing 1 day before TNBS administration. Visceral mechanosensitivity was assessed in vivo by quantifying visceromotor responses (VMR) to colorectal distension (CRD; 0- 80 mmHg). Statistical analysis was performed using the generalized estimating equations (SPSS software) and significance considered at a value of P <0.05. Results : Rats treated with intracolonic TNBS displayed significant colonic inflammation and increases in MPO activity compared with control rats ( P <0.01, N = 9/group). Vehicle- treated colitis rats displayed visceral hypersensitivity, as indicated by significantly elevated VMR to CRD, specifically at distension pressures of 20 mmHg ( P <0.05) and 40- 80 mmHg ( P <0.01; N = 9/group). Colitis rats administered APD371 twice daily had significantly reduced VMR to CRD compared with vehicle- treated colitis rats, with VMR normalized to control levels ( P <0.001, N = 9/group). In contrast, control rats treated twice daily with APD371 did not show altered visceral sensitivity to CRD ( P > 0.05, N = 8- 11 per group). Conclusion : Administration of APD371 reduced colitis- induced visceral hypersensitivity, suggesting that activation of CB2 causes antinociceptive actions in visceral sensory pathways. APD371, through its selectivity, is designed to provide pain relief without psychotropic effects and without the potential for dependence or abuse. Therefore, APD371 may provide a novel therapeutic treatment for IBD- associated abdominal pain.