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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

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

Douglas C. McVey, Patricia C. Schmid, Harald H. O. Schmid and Steven R. Vigna
Journal of Pharmacology and Experimental Therapeutics February 2003, 304 (2) 713-722; DOI: https://doi.org/10.1124/jpet.102.043893
Douglas C. McVey
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Patricia C. Schmid
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Harald H. O. Schmid
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Steven R. Vigna
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Abstract

Intraluminal administration of the endocannabinoidsN-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 antagonistsN-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (SR141716) andN-[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.

Footnotes

  • This work was supported by a Veterans Affairs Merit Review Grant (to S.R.V.), National Institutes of Health Grants DK-50265 (to S.R.V.) and GM-45741 (to H.H.O.S.), and by the Hormel Foundation (to H.H.O.S.).

  • DOI: 10.1124/jpet.102.043893

  • Abbreviations:
    SP
    substance P
    VR1
    vanilloid receptor subtype 1
    CB
    cannabinoid
    2-AG
    2-arachidonoylglycerol
    FAAH
    fatty acid amide hydrolase
    MAFP
    methyl arachidonyl fluorophosphonate
    PMSF
    phenylmethanesulfonyl fluoride
    DMSO
    dimethyl sulfoxide
    MPO
    myeloperoxidase
    NK-1R
    neurokinin-1 receptor
    NK-1R-ir
    neurokinin-1 receptor-1R-immunoreactive
    NAE
    N-acylethanolamine
    MAG
    monoacylglycerol
    tBDMS
    tert-butyldimethylsilyl
    NK-1
    neurokinin-1
    • Received August 4, 2002.
    • Accepted October 3, 2002.
  • U.S. Government
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Journal of Pharmacology and Experimental Therapeutics: 304 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 304, Issue 2
1 Feb 2003
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

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

Douglas C. McVey, Patricia C. Schmid, Harald H. O. Schmid and Steven R. Vigna
Journal of Pharmacology and Experimental Therapeutics February 1, 2003, 304 (2) 713-722; DOI: https://doi.org/10.1124/jpet.102.043893

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

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

Douglas C. McVey, Patricia C. Schmid, Harald H. O. Schmid and Steven R. Vigna
Journal of Pharmacology and Experimental Therapeutics February 1, 2003, 304 (2) 713-722; DOI: https://doi.org/10.1124/jpet.102.043893
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