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

Abstract

Background Cannabinoids have been traditionally used for the treatment of gastrointestinal (GI) symptoms, but the associated central effects, through cannabinoid-1 receptors (CB1R), constitute an important drawback. Our aims were to characterize the effects of the recently developed highly potent long-acting megagonist AM841 on GI motor function and to determine its central effects in rats. Methods Male Wistar rats were used for in vitro and in vivo studies. The effect of AM841 was tested on electrically-induced twitch contractions of GI preparations (in vitro) and on GI motility measured radiographically after contrast administration (in vivo). Central effects of AM841 were evaluated using the cannabinoid tetrad. The non-selective cannabinoid agonist WIN 55,212-2 (WIN) was used for comparison. The CB1R (AM251) and CB2R (AM630) antagonists were used to characterize cannabinoid receptor-mediated effects of AM841. Key results AM841 dose-dependently reduced in vitro contractile activity of rat GI preparations via CB1R, but not CB2R or opioid receptors. In vivo, AM841 acutely and potently reduced gastric emptying and intestinal transit in a dose-dependent and AM251-sensitive manner. The in vivo GI effects of AM841 at 0.1 mg kg−1 were comparable to those induced by WIN at 5 mg kg−1. However, at this dose, AM841 did not induce any sign of the cannabinoid tetrad, whereas WIN induced significant central effects. Conclusions & Inferences The CB1R megagonist AM841 may potently depress GI motor function in the absence of central effects. This effect may be mediated peripherally and may be useful in the treatment of GI motility disorders.

Tracking gastrointestinal transit of solids in aged rats as pharmacological models of chronic dysmotility

“…The high resolution X‐ray imaging utilized in this study provided clear localization of magnetic beads and allowed discrimination of the extent to which ingested contents had travelled over time, without the need for postmortem confirmation. This is a major technical advantage for future studies, building on previous X‐ray studies using liquid suspensions . We note the recent use of non‐invasive 3D X‐ray micro computed tomography imaging with contrasting metallic particles to assess gastric retention in rats …”

“…To study effective treatments to improve GI transit we require animal models of dysmotility that translate to humans and mimic the transit of solid foods. Many current methods to measure GI transit track the progress of liquid slurries which transit differently than solid foods. Furthermore, to determine GI transit to a particular location these methods require postmortem evaluation.…”

Chemotherapy-Induced Constipation and Diarrhea: Pathophysiology, Current and Emerging Treatments

“…Although the activity of the endocannabinoid system varies between species and different regions of the GI tract within the same species, activation of CB 1 receptors coupled to cholinergic motor neurons has been found to inhibit excitatory neuromuscular transmission in human colonic circular muscle (Hinds et al, 2006) and inhibit colonic propulsion in mice and rat (Pinto et al, 2002; Abalo et al, 2015). In recent human trials, dronabinol, a non-selective cannabinoid receptor agonist, was found to inhibit colonic motility in both healthy subjects (Esfandyari et al, 2006, 2007) and patients with IBS-related diarrhea (IBS-D) (Wong et al, 2011).…”

Radiographic dose‐dependency study of loperamide effects on gastrointestinal motor function in the rat. Temporal relationship with nausea‐like behavior

“…In our study, using conscious rats, loperamide effects were clearly dose‐dependent and significant for all doses. The effects of Lop 1 and Lop 10 on gastrointestinal motility were comparable to those of the cannabinoid agonist AM841 at 0.1 and 0.5 mg kg −1 , respectively, where only AM841 at 0.5 mg kg −1 was able to induce significant antinociception, hypothermia, and catalepsy . At 10 mg kg −1 , morphine effects on gastrointestinal motility were not as intense as those of loperamide at the same dose .…”

“…Loperamide induced CNS effects at the highest dose tested in all tests except for catalepsy. Catalepsy is characteristically induced by antipsychotics and, less intensely, by cannabinoids, although the synthetic cannabinoid CB1 receptor agonist AM841 did not exert this or other central effects when used at relatively low doses, yet able to potently suppress gastrointestinal motility . Catalepsy may be induced by morphine, at large amounts (but mechanisms differ from those triggered by antipsychotics like haloperidol).…”