Activation of cannabinoid 2 receptor relieves colonic hypermotility in a rat model of irritable bowel syndrome

Abstract

Background Irritable bowel syndrome (IBS) is a common disease with intestinal dysmotility, whose mechanism remains elusive. The endocannabinoid system is emerging as an important modulator of gastrointestinal (GI) motility in multiple diseases, but its involvement in IBS is unknown. We aimed to determine whether cannabinoid 2 (CB2) receptor modulates intestinal motility associated with stress‐induced IBS. Methods A rat IBS model was established by chronic water avoidance stress (WAS). Colonic pathological alterations were detected histologically and intestinal motility was assessed by intestinal transit time (ITT) and fecal water content (FWC). Visceral sensitivity was determined by visceromotor response (VMR) to colorectal distension (CRD). Real‐time PCR, western blot, and immunostaining were performed to identify colonic CB2 receptor expression. Colonic muscle strip contractility was studied by isometric transducers and nitric oxide (NO) was detected by the Griess test. The effects of AM1241, a selective agonist of CB2 receptors, on colonic motility were examined. Key Results After 10 days of WAS exposure, ITT was decreased and FWC elevated while VMR magnitude in response to CRD was significantly enhanced. Colon CB2 protein and mRNA levels increased and density of CB2‐positive macrophages in the mucosa and enteric neurons in the myenteric plexus was higher than in controls. Pharmacological enhancement of CB2 activity by AM1241 relieved colonic hypermotility in WAS rats in a concentration‐dependent manner via inhibition of p38 phosphorylation and elevation of NO production. Conclusion CB2 receptor may exert an important inhibitory effect in stress‐induced colonic hypermotility by modulating NO synthesis through p38 mitogen‐activated protein kinase signaling. AM1241 could be used as a potential drug to treat disorders with colonic hypermotility.

Cannabinoid‐induced relief of hypermotility in a rat model of the irritable bowel syndrome

“…CB2 receptors mediate the anti‐inflammatory effects of Δ 9 ‐THC . However, the paper by Lin et al in this issue of Neurogastroenterology and Motility shows that Δ 9 ‐THC acting at CB2 receptors can alter gastrointestinal motility and sensation in a rat model of the irritable bowel syndrome (IBS) . These studies confirm previous work showing that CB2 receptors are expressed by enteric neurons and by mesenteric afferent nerves supplying the gut .…”

Veränderungen der Darm-Gehirn-Achse beim Reizdarmsyndrom – Ein Update

“…Hierüber können Angsterkrankungen und Depressionen Motilitätsstörungen verursachen [32]. Eine kürzlich publizierte Studie konnte im Tiermodell zeigen, dass Cannabinoid-2-Rezeptor-Agonisten einen bedeutenden inhibitorischen Effekt auf eine gesteigerte Motilität im Kolon durch Modulation der NO-Synthese haben können [33].…”

Dysregulated cystathionine‐β‐synthase/hydrogen sulfide signaling promotes chronic stress‐induced colonic hypermotility in rats

“…The enteric nervous system (ENS), which is regarded as a "brain-in-thegut," represents an important candidate mechanism responsible for intestinal dysmotility in IBS. 2,3 Hydrogen sulfide (H 2 S), the third endogenous gasotransmitter, exerts its effects in a wide range of physiological systems (such as the nervous, cardiovascular, hepatic, and immune 4 ) and pathological processes (such as inflammation, cancer, pain, 5 and metabolic processes 6 ). Accordingly, H 2 S has attracted substantial interest as a potential target for pharmacological manipulation.…”

“…Presently, the mechanism of IBS is poorly understood; however, psychological distress and disrupted brain‐gut axis have been reported to play a pivotal role in IBS etiopathology. The enteric nervous system (ENS), which is regarded as a “brain‐in‐the‐gut,” represents an important candidate mechanism responsible for intestinal dysmotility in IBS 2,3 …”