Intest Res.  2022 Oct;20(4):392-417. 10.5217/ir.2021.00160.

Involvement of the cannabinoid system in chronic inflammatory intestinal diseases: opportunities for new therapies

• Lima PA
• Berg BB
• Castor MGMe

• KMID: 2535815
• DOI: http://doi.org/10.5217/ir.2021.00160

Abstract

The components of the endogenous cannabinoid system are widely expressed in the gastrointestinal tract contributing to local homeostasis. In general, cannabinoids exert inhibitory actions in the gastrointestinal tract, inducing anti-inflammatory, antiemetic, antisecretory, and antiproliferative effects. Therefore, cannabinoids are interesting pharmacological compounds for the treatment of several acute intestinal disorders, such as dysmotility, emesis, and abdominal pain. Likewise, the role of cannabinoids in the treatment of chronic intestinal diseases, such as irritable bowel syndrome and inflammatory bowel disease, is also under investigation. Patients with chronic intestinal inflammatory diseases present impaired quality of life, and mental health issues are commonly associated with long-term chronic diseases. The complex pathophysiology of these diseases contributes to difficulties in diagnosis and, therefore, in the choice of a satisfactory treatment. Thus, this article reviews the involvement of the cannabinoid system in chronic inflammatory diseases that affect the gastrointestinal tract and highlights possible therapeutic approaches related to the use of cannabinoids.

Keyword

Inflammatory bowel disease; Cannabinoid system; Cannabinoids; Inflammation; Chronic intestinal disease

Figure

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  Fig. 1. The canonical signaling pathway of cannabinoid receptors (CBRs). Here we display a largely simplified example of the main signaling pathways initiated by the binding of a cannabinoid agonist to a CBR, either CB1R or CB2R. The canonical binding pathway involves the coupling of Gi/0 proteins. The α subunits will display different actions, as α0 will lead to inactivation of Ca2+ voltage related channels and K+ channels. Activation; αi will lead to inhibition of adenylate cyclase (AC) and 3’,5’-cyclic adenosine monophosphate (cAMP) formation, this will inhibit the MEK/ERK/MAPK cascade, resulting in the cellular survival/death decision. In some instances, CBRs might couple to Gs proteins and, therefore, αs will stimulate cAMP [6,23,35-38]. PKA, protein kinase A; MEK, mitogen-activated protein kinase kinase; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase.

• 

  Fig. 2. Synthesis of 2-arachidonyl glycerol (2-AG) and anandamide (AEA). Glycerol-3-phosphate (G3P) by acyl-CoA:glycerol-3-phosphate acyltransferase (GPAT) action produces lysophosphatidic acid (LPA), and its acylation by acyl-CoA:lysophosphatidic acid acyltransferase (LPAAT) creates phosphatidic acid (PA). This molecule can be converted into 2-AG by PA phosphohydrolase or into diacylglycerol (DAG) by phosphatidic acid phosphatase (PAP). DAG will then interact with cytidine 5’-diphosphate (CDP)-ethanolamine, producing phosphatidylethanolamine (PE) that will be converted into N-arachidonoyl-phosphatidylethanolamine (NAPE) by NAT. Finally, NAPE-PLD will convert NAPE into AEA.

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  Fig. 3. Role of cannabinoid receptor in the gut. (a) Control of endocannabinoid signaling in the intestines by cholinergic innervation of efferent vagal fibers, releasing and acetylcholine (ACh), and activating muscarinic receptors that, in time, will stimulate the conversion of 1-stearoyl-2-arachidonoyl-sn-glycerol (SAG) in 2-arachidonyl glycerol (2-AG), by the enzyme diacylglycerol lipase (DAGL). 2-AG will bind to cannabinoid receptor 1 (CBR1), promoting the inhibition of satiety [54]. (b) CB1R receptors in the nervous fibers located in the myenteric plexus will regulate intestinal motility [53,55]. (c) Cannabinoid receptor 2 (CBR2) is expressed in the submucous-plexus and immune cells. Its expression is further induced in epithelial cells during inflammatory events [29]. ECS, endocannabinoid system.

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  Fig. 4. Cannabinoid agonists effects in the regulations of intestinal inflammatory diseases. Upon activation, both cannabinoid receptors 1 and 2 (CB1R and CB2R) will modulate several pathways and endogenous mechanisms leading to the reductions of proinflammatory cytokines, interleukins (ILs), oxidative stress molecules and inflammatory infiltrate. iNOS, induced nitric oxide synthase; NO, nitric oxide; ROS, reactive oxygen species; NAG, N-acetylglucosaminidase; MPO, myeloperoxidase; SOD, superoxide dismutase.

• 

  Fig. 5. Schematic representation of endocannabinoid metabolic pathways. (A) Synthesis of the endocannabinoid system (ECs) and enzymes enrolled in endocannabinoid hydrolysis in neurons; (B) overall representation of synthesis and degradation of endocannabinoids in the gastrointestinal tract (GI) tract. The cannabinoid receptor 1 (CB1R) is expressed in mostly all the GI tract, especially in the colon, where it can be found in epithelial cells, smooth muscle, and submucosal–myenteric plexus [135]. Although cannabinoid receptor 2 (CB2R) expression is found in immune cells, such as lymphocytes and antigen-presenting cells (APCs), it can also be found in the enteric nervous system [62,136]. The endocannabinoid precursors are produced by the remodeling of phospholipids and will be produced on demand. N-acyl-phosphatidylethanolamine-selective phospholipase D (NAPE-PLD) is responsible for the synthesis of ECs such as anandamide (AEA), oeoylethanolamide (OEA), and palmitoylethanolamide (PEA); and diacylglycerol lipase (DAGL) will lead to 2-arachidonyl glycerol (2-AG). The catabolism of these first ECs will be mediated by fatty acid amide hydrolase (FAAH), expressed through the GI tract, but it can also occur by other enzymes such as cyclooxygenase 2 (COX-2). 2-AG is mainly catabolized by monoacylglycerol lipase (MAGL), and this enzyme is expressed from the epithelium to the muscle layers and enteric neurons [24,137]. AA, arachidonic acid; NAAA, N-acylethanolamine acid amide hydrolase; PLC, phospholipase C; DAG, diacylglycerol; PI, phosphatidylinositol; CDTA, calcium-dependent transacylase; PE, phosphatidylethanolamine.

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