Rapid communication

Inhibition of histamine-stimulated gastric acid secretion by Δ⁹-tetrahydrocannabinol in rat isolated stomach

Cannabis sativa has long been known for its psychotropic effect. Only recently with the discovery of the cannabinoid receptors, their endogenous legends and the enzymes responsible for their synthesis and degradation, the role of this ‘endocannabinoid system’ in different pathophysiologic processes is beginning to be delineated. There is evidence that CB₁ receptor stimulation with synthetic cannabinoids or Cannabis sativa extracts rich in Δ⁹-tetrahydrocannabinol inhibit gastric acid secretion in humans and experimental animals. This is specially seen when gastric acid secretion is stimulated by pentagastrin, carbachol or 2-deoxy-d-glucose. Cannabis and/or cannabinoids protect the gastric mucosa against noxious challenge with non-steroidal anti-inflammatory drugs, ethanol as well as against stress-induced mucosal damage. Cannabis/cannabinoids might protect the gastric mucosa by virtue of its antisecretory, antioxidant, anti-inflammatory, and vasodilator properties.

The purpose of this review is to discuss the cellular synthesis and inactivation of two putative endogenous ligands of the cannabinoid receptor, N-arachidonylethanolamine (AEA) and 2-arachidonylglycerol (2-AG). Both ligands are synthesized by neurons and brain tissue in response to increased intracellular calcium concentrations. Both ligands are substrates for fatty acid amide hydrolase (FAAH). Both AEA and 2-AG bind to the neuronal form of the cannabinoid receptor (CB1). AEA binds the receptor with moderate affinity and has the characteristics of a partial agonist, whereas, 2-AG binds with low affinity but exhibits full efficacy. Two possible physiological roles of the endocannabinoids and the CB1 receptor are discussed: the regulation of gestation and the regulation of gastrointestinal motility.

We investigated involvement of the autonomic nervous system in gastric motor and cardiovascular responses to Δ⁹-tetrahydrocannabinol (Δ⁹-THC) in anesthetized rats. Intravenously administered Δ⁹-THC evoked long-lasting decreases in intragastric pressure and pyloric contractility, bradycardia, and hypotension. The changes in gastric motor function and bradycardia were abolished by vagotomy and ganglionic blockade, whereas spinal cord transection prevented the hypotensive response. Administered intravenously alone, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide, a putative cannabinoid CB₁ receptor antagonist, evoked transient decrease in intragastric pressure, and hypertension that was associated with bradycardia. However, this agent completely blocked the gastric motor and cardiovascular responses to intravenous Δ⁹-THC. Application of Δ⁹-THC to the dorsal surface of the medulla resulted in small and short-lasting decreases in gastric motor and cardiovascular function. We conclude that the decrease in gastric motor function and bradycardia are partially due to an action of Δ⁹-THC in the dorsal medulla and that intact vagal nerves are required. The hypotension was mediated through sympathetic pathways. Both gastric motor and cardiovascular effects of peripherally administered Δ⁹-THC seem to be mediated through cannabinoid CB₁ receptors.