Inhibiting fatty acid amide hydrolase normalizes endotoxin‐induced enhanced gastrointestinal motility in mice

Abstract

BACKGROUND AND PURPOSEGastrointestinal (GI) motility is regulated in part by fatty acid ethanolamides (FAEs), including the endocannabinoid (EC) anandamide (AEA). The actions of FAEs are terminated by fatty acid amide hydrolase (FAAH). We investigated the actions of the novel FAAH inhibitor AM3506 on normal and enhanced GI motility. EXPERIMENTAL APPROACHWe examined the effect of AM3506 on electrically-evoked contractility in vitro and GI transit and colonic faecal output in vivo, in normal and FAAH-deficient mice treated with saline or LPS (100 mg·kg KEY RESULTSFAAH was dominantly expressed in the enteric nervous system; its mRNA levels were higher in the ileum than the colon. LPS enhanced ileal contractility in the absence of overt inflammation. AM3506 reversed the enhanced electrically-evoked contractions of the ileum through CB1 and CB2 receptors. LPS increased the rate of upper GI transit and faecal output. AM3506 normalized the enhanced GI transit through CB1 and CB2 receptors and faecal output through CB1 receptors. LPS did not increase GI transit in FAAH-deficient mice. CONCLUSIONS AND IMPLICATIONSInhibiting FAAH normalizes various parameters of GI dysmotility in intestinal pathophysiology. Inhibition of FAAH represents a new approach to the treatment of disordered intestinal motility.

The endocannabinoid system in inflammatory bowel diseases: from pathophysiology to therapeutic opportunity

“…For instance, in lipopolysaccharide (LPS)-induced intestinal inflammation, hypermotility was normalized following CB 2 (but not CB 1 ) activation [19,20], whereas in croton oil-induced hypermotility CB 2 antagonism did not reverse the effect of the cannabinoid agonist CP55,940 [8]. In another study of LPS-induced inflammation, the FAAH inhibitor AM3506 normalized hypermotility in a CB 1 -and CB 2 -dependent manner, whereas colonic propulsion was CB 1 -dependent [21]. Interestingly, the effect of cannabinoids in cases of inflammatory hypermotility occurred at lower doses than in control states [8,22].…”

Biochemical Characterisation and Whole Genome Expression Profiling of Cultured Skin Fibroblasts from Two South African Adults with Urinary 3-Hydroxyisovaleric Acid and 3-Methylcrotonylglycine

“…The overexpression of fatty acid amide hydrolases can compromise innate immunity in Arabidopsis [83]. Furthermore, inhibition of FAAH/FAAH2 seems to normalize cardiovascular function in hypertensive rats as well as normalise endotoxin-induced enhanced gastrointestinal motility in mice [84]. Strong associations between aberrant regulation of FAAH/FAAH2 and alcohol and substance dependency, as well as obesity [85] have been made.…”

The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review

“…Systemic (i.p.) administration of LPS causes an increased upper gastrointestinal transit and total stool weight that is blocked by the FAAH inhibitor AM3506 in an AM251-sensitive manner (Bashashati et al 2012). This route of LPS administration increases the mRNA for the inflammatory cytokine IL-1ß in the cerebellum and the lung, and these increases are reduced by prior treatment with the ABHD6 inhibitor WWL70 (Alhouayek et al 2013).…”