Cannabinoids Alleviate Experimentally Induced Intestinal Inflammation by Acting at Central and Peripheral Receptors

Abstract

Background and AimsIn an attempt to further investigate the role of cannabinoid (CB) system in the pathogenesis of inflammatory bowel diseases, we employed two recently developed ligands, AM841 (a covalently acting CB agonist) and CB13 (a peripherally-restricted CB agonist) to establish whether central and peripheral CB sites are involved in the anti-inflammatory action in the intestine.Methods and ResultsAM841 (0.01, 0.1 and 1 mg/kg, i.p.) significantly decreased inflammation scores in dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-treated mice when administered before induction of colitis or as a treatment of existing intestinal inflammation. The effect was absent in CB1, CB2 and CB1/2-deficient mice. A peripherally-restricted agonist CB13 did not alleviate colitis when given i.p. (0.1 mg/kg), but significantly decreased inflammation score after central administration (0.1 µg/animal).ConclusionsThis is the first evidence that central and peripheral CB receptors are responsible for the protective and therapeutic action of cannabinoids in mouse models of colitis. Our observations provide new insight to CB pharmacology and validate the use of novel ligands AM841 and CB13 as potent tools in CB-related research.

In vitro and non‐invasive in vivo effects of the cannabinoid‐1 receptor agonist AM841 on gastrointestinal motor function in the rat

“…injection of vehicle (30 μl kg −1 of Tocrisolve® in saline solution, see below), AM841 (0.1 or 1 mg kg −1 ) or WIN (5 mg kg −1 ), and alterations in GI motor function were radiographically recorded (see below). Doses of AM841 were selected based on previous studies (29, 30) and own pilot experiments.…”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…When activated, the ECS reduces intestinal inflammation (264), and both central and peripheral cannabinoid receptors are responsible for the beneficial action of cannabinoid receptor agonists in mouse models of colitis (264). Indeed, the ECS is implicated in inflammatory bowel disease pathogenesis (9), and in several gut diseases the components of this system are upregulated, as in the case of AEA, but not 2-AG, levels in biopsies from the inflamed colon of patients with ulcerative colitis (172), or of AEA levels (171) and CB1 and CB2 expression (50) during active celiac disease.…”

Medical Cannabis and Cannabinoids: An Option for the Treatment of Inflammatory Bowel Disease and Cancer of the Colon?

“…This problem might be circumvented by using peripherally acting cannabinoids, a strategy that seems highly plausible considering the prominent presence of the ECS in the gut. However, GI motility is strongly influenced by central CB 1 [82], and peripherally restricted agonists to CB 1 /CB 2 that were applied intraperitoneally failed to improve inflammation in experimental models of intestinal inflammation [83,84]. Instead, they were protective when applied intracerebroventricularly [84].…”

“…However, GI motility is strongly influenced by central CB 1 [82], and peripherally restricted agonists to CB 1 /CB 2 that were applied intraperitoneally failed to improve inflammation in experimental models of intestinal inflammation [83,84]. Instead, they were protective when applied intracerebroventricularly [84]. In addition, CB 1 deficiency in the vagal nerve slowed GI motility [85].…”