Endocannabinoid-related compounds in gastrointestinal diseases

Abstract

The endocannabinoid system (ECS) is an endogenous signalling pathway involved in the control of several gastrointestinal (GI) functions at both peripheral and central levels. In recent years, it has become apparent that the ECS is pivotal in the regulation of GI motility, secretion and sensitivity, but endocannabinoids (ECs) are also involved in the regulation of intestinal inflammation and mucosal barrier permeability, suggesting their role in the pathophysiology of both functional and organic GI disorders. Genetic studies in patients with irritable bowel syndrome (IBS) or inflammatory bowel disease have indeed shown significant associations with polymorphisms or mutation in genes encoding for cannabinoid receptor or enzyme responsible for their catabolism, respectively. Furthermore, ongoing clinical trials are testing EC agonists/antagonists in the achievement of symptomatic relief from a number of GI symptoms. Despite this evidence, there is a lack of supportive RCTs and relevant data in human beings, and hence, the possible therapeutic application of these compounds is raising ethical, political and economic concerns. More recently, the identification of several EC-like compounds able to modulate ECS function without the typical central side effects of cannabino-mimetics has paved the way for emerging peripherally acting drugs. This review summarizes the possible mechanisms linking the ECS to GI disorders and describes the most recent advances in the manipulation of the ECS in the treatment of GI diseases.

Keywords: endocannabinoid system; functional gastrointestinal disorders; gastrointestinal pathophysiology; inflammatory bowel disease; non-alcoholic steatohepatitis.

Figure 1

Schematic overview of the enzymes involved in EC metabolism. Anandamide (AEA) and 2‐acylglycerol (2‐AG) are the two best‐recognized stereotypical ECs. Both are synthetized by hydrolysis from membrane lipid precursors, namely N‐arachidonoyl‐phosphatidylethanolamine (NArPE) and phosphatidylinositol‐4,5‐bisphosphate (PIP2) for AEA and 2‐AG, respectively. Both AEA and 2‐AG, after the binding with CB receptors, are rapidly removed by membrane transporters and converted into arachidonic acid by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively.

Figure 2

Biosynthesis and degradation of N‐acylethanolamides (NAEs) and possible points of interaction between AEA and its related compounds. Similar to AEA, N‐palmitoylethanolamine (PEA) and N‐oleoylethanolamine (OEA) are synthesized by N‐acylphosphatidylethanolamine‐specific phospholipase D (NAPE‐PLD) from membrane precursors. Unlike AEA, PEA and OEA exhibit no binding affinity on CB1/CB2 receptors, but they can enhance AEA activity at TRPV1 receptors. PEA and OEA are degraded by either fatty acid amide hydrolase (FAAH) or N‐acetylethanolamine‐hydrolysing acid amidase (NAAA). By competing with AEA for FAAH (mainly OEA) or by down‐regulating FAAH expression (predominantly PEA), they can increase AEA levels.