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Targeting fatty acid amide hydrolase and transient receptor potential vanilloid‐1 simultaneously to modulate colonic motility and visceral sensation in the mouse: A pharmacological intervention with N‐arachidonoyl‐serotonin ( AA ‐5‐ HT )
Author(s) -
Bashashati M.,
Fichna J.,
Piscitelli F.,
Capasso R.,
Izzo A. A.,
Sibaev A.,
Timmermans J.P.,
Cenac N.,
Vergnolle N.,
Di Marzo V.,
Storr M.
Publication year - 2017
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1111/nmo.13148
Subject(s) - fatty acid amide hydrolase , chemistry , trpv , transient receptor potential channel , endocannabinoid system , pharmacology , anandamide , trpv1 , endocrinology , medicine , antagonist , biochemistry , receptor , cannabinoid receptor
Background Endocannabinoid anandamide ( AEA ) inhibits intestinal motility and visceral pain, but it may also be proalgesic through transient receptor potential vanilloid‐1 ( TRPV 1). AEA is degraded by fatty acid amide hydrolase ( FAAH ). This study explored whether dual inhibition of FAAH and TRPV 1 reduces diarrhea and abdominal pain. Methods Immunostaining was performed on myenteric plexus of the mouse colon. The effects of the dual FAAH / TRPV 1 inhibitor AA ‐5‐ HT on electrically induced contractility, excitatory junction potential ( EJP ) and fast (f) and slow (s) inhibitory junction potentials ( IJP ) in the mouse colon , colonic propulsion and visceromotor response ( VMR ) to rectal distension were studied. The colonic levels of endocannabinoids and fatty acid amides were measured. Key Results CB 1‐positive neurons exhibited TRPV 1; only some TRPV 1 positive neurons did not express CB 1. CB 1 and FAAH did not colocalize. AA ‐5‐ HT (100 nM ‐10 μM) decreased colonic contractility by ~60%; this effect was abolished by TRPV 1 antagonist 5′‐ IRTX , but not by CB 1 antagonist, SR 141716. AA ‐5‐ HT (1 μM‐10 μM) inhibited EJP by ~30% and IJP s by ~50%. The effects of AA ‐5‐ HT on junction potentials were reversed by SR 141716 and 5`‐ IRTX . AA ‐5‐ HT (20 mg/kg; i.p.) inhibited colonic propulsion by ~30%; SR 141716 but not 5`‐ IRTX reversed this effect. AA ‐5‐ HT decreased VMR by ~50%‐60%; these effects were not blocked by SR 141716 or 5`‐ IRTX . AA ‐5‐ HT increased AEA in the colon. Conclusions and Inferences The effects of AA ‐5‐ HT on visceral sensation and colonic motility are differentially mediated by CB 1, TRPV 1 and non‐ CB 1/ TRPV 1 mechanisms, possibly reflecting the distinct neuromodulatory roles of endocannabinoid and endovanilloid FAAH substrates in the mouse intestine.