The Role of the Endocannabinoid System in the Brain–Gut Axis

Abstract

The actions of cannabis are mediated by receptors that are part of an endogenous cannabinoid system. The endocannabinoid system (ECS) consists of the naturally occurring ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), their biosynthetic and degradative enzymes, and the cannabinoid receptors CB1 and CB2. The ECS is a widely distributed transmitter system that controls gut functions peripherally and centrally. It is an important physiologic regulator of gastrointestinal motility. Polymorphisms in the gene encoding CB1 (CNR1) have been associated with some forms of irritable bowel syndrome. The ECS is involved in the control of nausea and vomiting and visceral sensation. The homeostatic role of the ECS also extends to the control of intestinal inflammation. We review the mechanisms by which the ECS links stress and visceral pain. CB1 in sensory ganglia controls visceral sensation, and transcription of CNR1 is modified through epigenetic processes under conditions of chronic stress. These processes might link stress with abdominal pain. The ECS is also involved centrally in the manifestation of stress, and endocannabinoid signaling reduces the activity of hypothalamic–pituitary–adrenal pathways via actions in specific brain regions—notably the prefrontal cortex, amygdala, and hypothalamus. Agents that modulate the ECS are in early stages of development for treatment of gastrointestinal diseases. Increasing our understanding of the ECS will greatly advance our knowledge of interactions between the brain and gut and could lead to new treatments for gastrointestinal disorders.

Cutting Edge: Dysregulated Endocannabinoid-Rheostat for Plasmacytoid Dendritic Cell Activation in a Systemic Lupus Endophenotype

“…2-AG has been previously reported to affect cellular functions in different cell types through a myriad of receptors (Fig. 5A), for example, through engagement of cycloxygenase-2 (COX2) in myeloid cells by the 2-AG hydrolysis product arachidonic acid (10), through peroxisome proliferator-activated receptor a (PPARa) in mesenchymal stem cells (27), and the specific cannabinoid receptors CB1 and CB2 (28). We found that the 2-AGdriven resistive effect on pDC activation could not be reversed by the COX2-specific inhibitor valdecoxib (Fig.…”

Nutritional status‐dependent endocannabinoid signalling regulates the integration of rat visceral information

“…In addition, the eCB system plays a crucial role in the regulation of energy balance through central and peripheral mechanisms (Quarta et al . ; Sharkey & Wiley, ). Nutritional status causes dramatic changes in eCB signalling and related synaptic plasticity in brain regions involved in the sensing of nutrient availability.…”

“…Among several actors involved in synaptic plasticity, lipid messengers such as endocannabinoid (eCB) are key modulators of synaptic functions (Castillo et al 2012) where they mediate diverse forms of short and long-term changes in synaptic efficacy. In addition, the eCB system plays a crucial role in the regulation of energy balance through central and peripheral mechanisms (Quarta et al 2010;Sharkey & Wiley, 2016). Nutritional status causes dramatic changes in eCB signalling and related synaptic plasticity in brain regions involved in the sensing of nutrient availability.…”

Medical Cannabis and Cannabinoids: An Option for the Treatment of Inflammatory Bowel Disease and Cancer of the Colon?

“…The beneficial properties of cannabinoids on the gastrointestinal (GI) tract are built on the fact that the intestines are endowed with the endocannabinoid system (ECS), a regulatory network of cannabinoid receptors, enzymes, and ligands that play key roles in physiological as well as pathophysiological processes [1][2][3][4]. Thus, the gut expresses the classical cannabinoid receptors 1 and 2 (CB 1 , CB 2 ) and cannabinoid-responsive non-CB 1 /CB 2 receptors (G protein-coupled receptor 55 [GPR55], transient receptor potential cation channel subfamily V member 1 [TRPV1], and peroxisome proliferator-activated receptor gamma and alpha [PPARγ and PPARα]).…”