RESUMEN
BACKGROUND: In ancient medicine, extracts of the marijuana plant Cannabis sativa were used against diseases of the gastrointestinal (GI) tract. Today, our knowledge of the ingredients of the Cannabis plant has remarkably advanced enabling us to use a variety of herbal and synthetic cannabinoid (CB) compounds to study the endocannabinoid system (ECS), a physiologic entity that controls tissue homeostasis with the help of endogenously produced CBs and their receptors. After many anecdotal reports suggested beneficial effects of Cannabis in GI disorders, it was not surprising to discover that the GI tract accommodates and expresses all the components of the ECS. Cannabinoid receptors and their endogenous ligands, the endocannabinoids, participate in the regulation of GI motility, secretion, and the maintenance of the epithelial barrier integrity. In addition, other receptors, such as the transient receptor potential cation channel subfamily V member 1 (TRPV1), the peroxisome proliferator-activated receptor alpha (PPARα) and the G-protein coupled receptor 55 (GPR55), are important participants in the actions of CBs in the gut and critically determine the course of bowel inflammation and colon cancer. PURPOSE: The following review summarizes important and recent findings on the role of CB receptors and their ligands in the GI tract with emphasis on GI disorders, such as irritable bowel syndrome, inflammatory bowel disease, and colon cancer.
Asunto(s)
Moduladores de Receptores de Cannabinoides/uso terapéutico , Cannabinoides/metabolismo , Enfermedades Gastrointestinales/metabolismo , Tracto Gastrointestinal/metabolismo , Receptores de Cannabinoides/metabolismo , Transducción de Señal/fisiología , Animales , Moduladores de Receptores de Cannabinoides/farmacología , Cannabinoides/uso terapéutico , Endocannabinoides/metabolismo , Endocannabinoides/uso terapéutico , Enfermedades Gastrointestinales/tratamiento farmacológico , Motilidad Gastrointestinal/efectos de los fármacos , Motilidad Gastrointestinal/fisiología , Tracto Gastrointestinal/efectos de los fármacos , Humanos , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND AND PURPOSE: Monoglyceride lipase (MGL) degrades 2-arachidonoyl glycerol (2-AG), an endogenous agonist of cannabinoid receptors (CB1/2 ). Because the CB1 receptor is involved in the control of gut function, we investigated the effects of pharmacological inhibition and genetic deletion of MGL on intestinal motility. Furthermore, we determined whether defective 2-AG degradation affects µ-opioid receptor (µ receptor) signalling, a parallel pathway regulating gut motility. EXPERIMENTAL APPROACH: Gut motility was investigated by monitoring Evans Blue transit and colonic bead propulsion in response to MGL inhibition and CB1 receptor or µ receptor stimulation. Ileal contractility was investigated by electrical field stimulation. CB1 receptor expression in ileum and colon was assessed by immunohistochemical analyses. KEY RESULTS: Pharmacological inhibition of MGL slowed down whole gut transit in a CB1 receptor-dependent manner. Conversely, genetic deletion of MGL did not affect gut transit despite increased 2-AG levels. Notably, MGL deficiency caused complete insensitivity to CB1 receptor agonist-mediated inhibition of whole gut transit and ileal contractility suggesting local desensitization of CB1 receptors. Accordingly, immunohistochemical analyses of myenteric ganglia of MGL-deficient mice revealed that CB1 receptors were trapped in endocytic vesicles. Finally, MGL-deficient mice displayed accelerated colonic propulsion and were hypersensitive to µ receptor agonist-mediated inhibition of colonic motility. This phenotype was reproduced by chronic pharmacological inhibition of MGL. CONCLUSION AND IMPLICATIONS: Constantly elevated 2-AG levels induce severe desensitization of intestinal CB1 receptors and increased sensitivity to µ receptor-mediated inhibition of colonic motility. These changes should be considered when cannabinoid-based drugs are used in the therapy of gastrointestinal diseases.