In vitro functional evidence of neuronal cannabinoid CB1 receptors in human ileum |
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Authors: | Tiziano Croci Luciano Manara Giulio Aureggi Fabio Guagnini Murielle Rinaldi-Carmona Jean-Pierre Maffrand Gérard Le Fur Sylvain Mukenge Gianfranco Ferla |
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Affiliation: | 1.Research Center Sanofi Midy, Via G.B. Piranesi 38, 20137 Milan, Italy;2.Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy;3.Sanofi Recherche, 195 Route d''Espagne, 31036 Toulouse, France;4.Sanofi Recherche, 32–43 rue Marbeuf, 75374 Paris, France;5.Sanofi Recherche, 371 rue du Pr. J. Blayac, 34184 Montpellier, France |
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Abstract: | We investigated the effect of the cannabinoid agonist (+)WIN-55212-2 on human ileum longitudinal smooth muscle preparations, either electrically stimulated or contracted by carbachol. Electrical field stimulation mostly activated cholinergic neurons, since atropine and tetrodotoxin (TTX), alone or co-incubated, reduced twitch responses to a similar degree (85%). (+)WIN-55212-2 concentration-dependently inhibited twitch responses (IC50 73 nM), but had no additive effect with atropine or TTX. The cannabinoid CB1 receptor antagonist SR 141716 (pA2 8.2), but not the CB2 receptor antagonist, SR 144528, competitively antagonized twitch inhibition by (+)WIN-55212-2. Atropine but not (+)WIN-55212-2 or TTX prevented carbachol-induced tonic contraction. These results provide functional evidence of the existence of prejunctional cannabinoid CB1-receptors in the human ileum longitudinal smooth muscle. Agonist activation of these receptors prevents responses to electrical field stimulation, presumably by inhibiting acetylcholine release. SR 141716 is a potent and competitive antagonist of cannabinoid CB1 receptors naturally expressed in the human gut. |
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Keywords: | Cannabinoids CB1 receptors WIN-55212-2 SR 141716 SR 144528 human ileum |
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