Endocannabinoids induce ileitis in rats via the capsaicin receptor (VR1).
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 (2S,3S)-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.
McVey
Douglas C
DC
Department of Cell Biology and Medicine, Duke University Medical Center, Veterans Affairs Medical Center, Durham, North Carolina 27710, USA.
Schmid
Patricia C
PC
Schmid
Harald H O
HH
Vigna
Steven R
SR
D000818:Animals; D001095:Arachidonic Acids / Q000633:toxicity; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005231:Fatty Acids, Unsaturated / Q000633:toxicity*; D007079:Ileitis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D008297:Male; D053284:Polyunsaturated Alkamides; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D013373:Substance P / Q000378:metabolism
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005231:Fatty Acids, Unsaturated; D053284:Polyunsaturated Alkamides; D011955:Receptors, Drug; D013373:Substance P; C078814:anandamide