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Inhibiting fatty acid amide hydrolase normalizes endotoxin-induced enhanced gastrointestinal motility in mice.
Br J Pharmacol. 2012 Mar; 165(5):1556-71.BJ

Abstract

BACKGROUND AND PURPOSE

Gastrointestinal (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 APPROACH

We 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 µg·kg(-1), i.p.), in the presence and absence of cannabinoid (CB) receptor antagonists. mRNA expression was measured by quantitative real time-PCR, EC levels by liquid chromatography-MS and FAAH activity by the conversion of [(3)H]-AEA to [(3)H]-ethanolamine in intestinal extracts. FAAH expression was examined by immunohistochemistry.

KEY RESULTS

FAAH 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 CB(1) and CB(2) receptors. LPS increased the rate of upper GI transit and faecal output. AM3506 normalized the enhanced GI transit through CB(1) and CB(2) receptors and faecal output through CB(1) receptors. LPS did not increase GI transit in FAAH-deficient mice.

CONCLUSIONS AND IMPLICATIONS

Inhibiting FAAH normalizes various parameters of GI dysmotility in intestinal pathophysiology. Inhibition of FAAH represents a new approach to the treatment of disordered intestinal motility.

Authors+Show Affiliations

Hotchkiss Brain Institute and Snyder Institute of Infection, Immunity & Inflammation, Department of Physiology & Pharmacology, University Calgary, Calgary, AB, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21883147

Citation

Bashashati, M, et al. "Inhibiting Fatty Acid Amide Hydrolase Normalizes Endotoxin-induced Enhanced Gastrointestinal Motility in Mice." British Journal of Pharmacology, vol. 165, no. 5, 2012, pp. 1556-71.
Bashashati M, Storr MA, Nikas SP, et al. Inhibiting fatty acid amide hydrolase normalizes endotoxin-induced enhanced gastrointestinal motility in mice. Br J Pharmacol. 2012;165(5):1556-71.
Bashashati, M., Storr, M. A., Nikas, S. P., Wood, J. T., Godlewski, G., Liu, J., Ho, W., Keenan, C. M., Zhang, H., Alapafuja, S. O., Cravatt, B. F., Lutz, B., Mackie, K., Kunos, G., Patel, K. D., Makriyannis, A., Davison, J. S., & Sharkey, K. A. (2012). Inhibiting fatty acid amide hydrolase normalizes endotoxin-induced enhanced gastrointestinal motility in mice. British Journal of Pharmacology, 165(5), 1556-71. https://doi.org/10.1111/j.1476-5381.2011.01644.x
Bashashati M, et al. Inhibiting Fatty Acid Amide Hydrolase Normalizes Endotoxin-induced Enhanced Gastrointestinal Motility in Mice. Br J Pharmacol. 2012;165(5):1556-71. PubMed PMID: 21883147.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibiting fatty acid amide hydrolase normalizes endotoxin-induced enhanced gastrointestinal motility in mice. AU - Bashashati,M, AU - Storr,M A, AU - Nikas,S P, AU - Wood,J T, AU - Godlewski,G, AU - Liu,J, AU - Ho,W, AU - Keenan,C M, AU - Zhang,H, AU - Alapafuja,S O, AU - Cravatt,B F, AU - Lutz,B, AU - Mackie,K, AU - Kunos,G, AU - Patel,K D, AU - Makriyannis,A, AU - Davison,J S, AU - Sharkey,K A, PY - 2011/9/3/entrez PY - 2011/9/3/pubmed PY - 2012/9/8/medline SP - 1556 EP - 71 JF - British journal of pharmacology JO - Br J Pharmacol VL - 165 IS - 5 N2 - BACKGROUND AND PURPOSE: Gastrointestinal (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 APPROACH: We 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 µg·kg(-1), i.p.), in the presence and absence of cannabinoid (CB) receptor antagonists. mRNA expression was measured by quantitative real time-PCR, EC levels by liquid chromatography-MS and FAAH activity by the conversion of [(3)H]-AEA to [(3)H]-ethanolamine in intestinal extracts. FAAH expression was examined by immunohistochemistry. KEY RESULTS: FAAH 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 CB(1) and CB(2) receptors. LPS increased the rate of upper GI transit and faecal output. AM3506 normalized the enhanced GI transit through CB(1) and CB(2) receptors and faecal output through CB(1) receptors. LPS did not increase GI transit in FAAH-deficient mice. CONCLUSIONS AND IMPLICATIONS: Inhibiting FAAH normalizes various parameters of GI dysmotility in intestinal pathophysiology. Inhibition of FAAH represents a new approach to the treatment of disordered intestinal motility. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/21883147/Inhibiting_fatty_acid_amide_hydrolase_normalizes_endotoxin_induced_enhanced_gastrointestinal_motility_in_mice_ L2 - https://doi.org/10.1111/j.1476-5381.2011.01644.x DB - PRIME DP - Unbound Medicine ER -