The Contractile Effect of Anandamide in the Guinea‐Pig Small Intestine is Mediated by Prostanoids but not TRPV1 Receptors or Capsaicin‐Sensitive Nerves

Although exogenous and endogenous cannabinoid receptor agonists have well‐documented inhibitory effects on gastrointestinal motility, a TRPV1 receptor‐mediated excitatory action of anandamide (arachidonoyl ethanolamide, AEA) in the guinea‐pig ileum strip has also been described. We used in vitro capsaicin desensitization for assessing the possible participation of sensory neurons in the contractile effect of anandamide on the guinea‐pig whole ileum, as well as autonomic drugs and a cyclooxygenase inhibitor for characterizing this response. Isolated organ experiments were used with isotonic recording. Contractions induced by anandamide (1 or 10 μM) were strongly inhibited by tetrodotoxin, indomethacin or atropine plus a tachykinin NK₁ receptor antagonist, but weakly to moderately reduced by atropine alone and partly diminished by the fatty acid amide hydrolase inhibitor URB 597. Neither capsaicin pre‐treatment nor the TRPV1 receptor antagonist BCTC, the ganglionic blocking drug hexamethonium or cannabinoid (CB₁ or CB₂) receptor antagonists, influenced the effect of anandamide. It is concluded that the capsaicin‐insensitive, neuronal excitatory effect of anandamide in the intestine is most probably mediated by cyclooxygenase products. Such a mechanism may also play a role at other sites in the mammalian body.