In vitro functional evidence of neuronal cannabinoid CB₁ receptors in human ileum

Abstract

We investigated the eect of the cannabinoid agonist (+)WIN-55212-2 on human ileum longitudinal smooth muscle preparations, either electrically stimulated or contracted by carbachol. Electrical ®eld stimulation mostly activated cholinergic neurons, since atropine and tetrodotoxin (TTX), alone or coincubated, reduced twitch responses to a similar degree (85%). (+)WIN-55212-2 concentrationdependently inhibited twitch responses (IC 50 73 nM), but had no additive eect with atropine or TTX. The cannabinoid CB 1 receptor antagonist SR 141716 (pA 2 8.2), but not the CB 2 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 CB 1 -receptors in the human ileum longitudinal smooth muscle. Agonist activation of these receptors prevents responses to electrical ®eld stimulation, presumably by inhibiting acetylcholine release. SR 141716 is a potent and competitive antagonist of cannabinoid CB 1 receptors naturally expressed in the human gut.

Inhibition of Improgan Antinociception by the Cannabinoid (CB)1 AntagonistN-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A): Lack of Obligatory Role for Endocannabinoids Acting at CB1 Receptors

“…The supraspinal component is mediated by actions in the periaqueductal gray and rostral ventral medulla (Lichtman et al, 1996;Martin et al, 1998;Meng et al, 1998;Vaughan et al, 1999), regions that contain CB 1 receptors and that are known to function in descending analgesic pathways. The cannabinoid antagonist SR141716A inhibits CB 1 agonist actions both in vitro (e.g., in biochemical and isolated tissue assays; RinaldiCarmona et al, 1994;Croci et al, 1998) and in vivo (e.g., analgesia, catalepsy, and hypothermia; Compton et al, 1996;Lichtman and Martin, 1997;Martin et al, 1998;Welch et al, 1998). In the rostral ventral medulla, CB 1 agonists activate these pain-relieving circuits by disinhibition of GABAergic transmission (Adams et al, 1998;Meng et al, 1998;Vaughan et al, 1999) and by stimulation of descending noradrenergic activity (Lichtman and Martin, 1991).…”

Atomoxetine for treatment of marijuana dependence: A report on the efficacy and high incidence of gastrointestinal adverse events in a pilot study

“…It is known that marijuana (through CB1 activity) can reduce gut motility and thereby prolong exposure of atomoxetine to gastrointestinal mucosa, possibly leading to GI irritation that could further compound withdrawal related GI symptoms. (Croci et al, 1998;Izzo et al, 2000).…”

Acute Activation of Cannabinoid Receptors by Anandamide Reduces Gastrointestinal Motility and Improves Postprandial Glycemia in Mice

“…CB1Rs are expressed in the gastrointestinal tract of many species (12,14). Immunohistochemical studies indicate that the enteric nervous system is the main site of CB1R expression and could be the main site of action for cannabinoids in the gastrointestinal tract (13).…”

“…The presence of a functional ECS in the gastrointestinal tract has been pointed out in many species (12)(13)(14), and available evidence suggests that cannabinoids reduce gastric and intestinal motility (15,16), but the consequences on plasma glucose appearance were poorly studied. However, consistent data indicate the existence of a positive relationship between gastrointestinal motility and plasma glucose appearance in healthy and diabetic patients (17)(18)(19).…”