Monoglyceride lipase-deficiency causes desensitization of intestinal cannabinoid receptor type 1 and increased colonic μ-opioid receptor sensitivity.

BACKGROUND AND PURPOSE:

Monoglyceride lipase (MGL) degrades 2-arachidonoyl glycerol (2-AG), an endogenous agonist of cannabinoidreceptors (CB1/2 ). Since 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 were interested whether defective 2-AG degradation affects μ-opioid receptor (μ-receptor) signaling, a parallel pathway regulating gut motility.

EXPERIMENTAL APPROACH:

Gut motility was investigated by monitoring Evan’s 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 studied by immunohistochemical analyses.

KEY RESULTS:

Pharmacological inhibition of MGL slows down whole gut transit in a CB1 receptor-dependent manner. Conversely, genetic deletion of MGL does not affect gut transit despite increased 2-AG levels. Notably, MGL-deficiency causes 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 are trapped in endocytic vesicles. Finally, MGL-deficient mice display accelerated colonic propulsion and respond hypersensitive to μ-opioid receptor agonist-mediated inhibition of colonic motility. This phenotype can be reproduced by chronic pharmalogical 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 for the use of cannabinoid-based drugs in the therapy of gastrointestinal diseases.
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