Endocannabinoids Induce Ileitis in Rats via the Capsaicin Receptor (VR1)

• Published in: The Journal of pharmacology and experimental therapeutics 2003-02, Vol.304 (2), p.713-722
• Main Authors: McVey, Douglas C, Schmid, Patricia C, Schmid, Harald H O, Vigna, Steven R
• Format: Article
• Language: English
• Subjects: Animals; Arachidonic Acids - toxicity; Cannabinoid Receptor Modulators; Endocannabinoids; Fatty Acids, Unsaturated - toxicity; Ileitis - chemically induced; Ileitis - metabolism; Ileitis - pathology; In Vitro Techniques; Male; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Receptors, Drug - agonists; Receptors, Drug - antagonists & inhibitors; Receptors, Drug - metabolism; Substance P - metabolism; Substance P - secretion
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.102.043893

Intraluminal administration of the endocannabinoids N- arachidonoyl-ethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG) causes inflammation similar to that caused by Clostridium difficile toxin A in the rat ileum. The effects of anandamide and 2-AG were significantly inhibited by pretreatment with the specific capsaicin receptor (vanilloid receptor subtype 1; VR1) antagonist capsazepine. Pretreatment with the CB1 and CB2 cannabinoid receptor antagonists N- piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (SR141716) and N- [1S)- endo -1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528) did not affect the responses to anandamide. It has previously been shown that intraluminal toxin A stimulates substance P (SP) release from primary sensory neurons and that pretreatment with SP receptor [neurokinin (NK)-1 receptor] antagonists inhibits the inflammatory effects of toxin A. Anandamide stimulated SP release and this was blocked by capsazepine pretreatment. Also, pretreatment with the specific NK-1 receptor antagonist (2 S ,3 S )-3-([3,5-bis[trifluoromethyl)phenyl]methoxy)-2-phenylpiperidine (L-733,060) significantly inhibited the inflammatory effects of both toxin A and anandamide. Toxin A increased tissue concentrations of anandamide and 2-AG in the ileum, and these effects were enhanced after pretreatment with inhibitors of fatty acid amide hydrolase, a major endocannabinoid-degrading enzyme. The toxin A-stimulated release of anandamide but not 2-AG was selective over their congeners. These results demonstrate that the endocannabinoids anandamide and 2-AG stimulate intestinal primary sensory neurons via the capsaicin VR1 receptor to release SP, resulting in enteritis, and that endocannabinoids may mediate the inflammatory effects of toxin A.