The endocannabinoid system and gut–brain signalling

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The endocannabinoid system (ECS) consists of cannabinoid receptors, endogenous ligands and the biosynthetic and metabolic enzymes for their formation and degradation. Within the gastrointestinal (GI) tract, the ECS is involved in the regulation of motility, secretion, sensation, emesis, satiety and inflammation. Recent studies examining the ECS in the gut–brain axis have shed new light on this system and reveal many facets of regulation that are amenable to targeting by pharmacological interventions that may prove valuable for the treatment of GI disorders. In particular, it has been shown that endocannabinoid levels in the brain and gut vary according to states of satiety, and in conditions of diarrhea, emesis and inflammation. The expression of cannabinoid (CB)1 receptors on vagal afferents is controlled by the states of satiety and by gut peptides such as cholecystokinin and ghrelin. Vagal control of gut motor function and emesis is regulated by endocannabinoids in the brainstem acting on CB1, CB2 and transient receptor potential vanilloid (TRPV)-1 receptors. The ECS is involved in the modulation of visceral sensation and likely contributes to effects of stress on GI function. This review examines recent developments in our understanding of the ECS in gut–brain signalling.

Introduction

It has been known for centuries that activity of the Cannabis plant and its extracts could alleviate symptoms of gastrointestinal disease, whilst at the same time promoting appetite. The discovery in the early 1960s that Δ9-tetrahydrocannabinol (THC) was the major psychoactive component of Cannabis was a significant milestone in establishing how Cannabis exerted its effects. Nearly 30 years later, the mechanism of how THC gave rise to its cellular actions was revealed with the identification and cloning of two G protein-coupled receptors, the cannabinoid (CB)1 and CB2 receptors. When the distribution of these receptors was first examined, the CB1 receptor was found to be largely confined to nervous tissues and highly expressed in the brain, whereas the CB2 receptor was expressed on cells and organs of the immune system. Endogenous ligands for these receptors were soon discovered and found to be fatty acids derived from membrane lipids. These compounds were named endocannabinoids, and together with their receptors, biosynthetic enzymes and uptake and degradation systems are described as the endocannabinoid system (ECS) [1, 2, 3].

The gut–brain axis consists of the neural and humoral pathways that link the gut to the central nervous system in a reciprocal relationship that is recognized as an integrated system for homeostatic and defensive regulation of the body [4]. More recently, the gut–brain axis has been implicated in stress-related control of gut motor and epithelial barrier function [5], contributing to allostasis and the dynamic adaptation to stresses of a pathophysiological and/or psychological nature [6]. Within the gastrointestinal (GI) tract, the ECS has been reported to be involved in the regulation of motility, secretion, sensation, emesis, satiety and inflammation [7•, 8, 9•]. Relatively few studies have examined the ECS in the gut–brain axis, but those studies have shed new light on this system and reveal many facets of regulation that are amenable to targeting by pharmacological interventions that may prove valuable for the treatment of GI-related disorders. In this review we will provide a concise account of some of the recent developments in our understanding of the role of the ECS in gut–brain signalling.

Section snippets

Endocannabinoids in the gut–brain axis

Anandamide (N-arachidonoylethanolamide, AEA) was the original ‘endocannabinoid’, found in both the brain and gut [3]. Chemically similar compounds formed from the transfer of fatty acid to phosphatidylethanolamine, include palmitoylethanolamide (PEA) and oleylethanolamide (OEA) [10, 11], but neither of these N-acylethanolamides are cannabinoid receptor ligands, though OEA derived from the GI tract is important in the regulation of food intake, acting via the vagus nerve [10]. The second class

Endocannabinoid levels in the gut–brain axis are regulated in health and disease

The levels of endocannabinoids in the gut–brain axis and their control have not been examined extensively, but published data shows that they are regulated in health and disease. In the gut there are regional variations in the levels of endocannabinoids with 2-AG being higher in the ileum than the colon, and AEA being considerably higher in the colon than the ileum [14, 15]. Endocannabinoid levels in the gut have been examined in various animal models of inflammation, emesis and in fed and

Vagal afferent neurons express CB1 receptors that are regulated by food intake

The peripheral site of action of endocannabinoids, lipid mediators and many gut hormones that regulate food intake are the terminals of vagal afferents in the GI tract. The expression of CB1 receptors on the cell bodies of vagal afferent neurons in the nodose ganglion was first reported by Partosoedarso et al. [31]. They made the interesting observation that in the ferret, the CB1 receptor was largely transported to the peripheral terminals of the vagus, rather than the central terminals,

Vagal control of gut motor function is regulated by endocannabinoids in the brainstem

Vagal afferent input from the GI tract terminates in the NTS, a complex integrative centre that projects widely and has numerous inputs from the brainstem and higher centres [34, 35]. Vagal motor neurons lie in columns in the dorsal motor nucleus of the vagus (DMN) that receives monosynaptic and polysynaptic input from the NTS, and produces excitatory or inhibitory output to the GI tract [35]. Application of cannabinoids to the dorsal vagal complex modifies gastric motility [36], lower

Endocannabinoids inhibit emesis through CB1, CB2 and TRPV1 receptors

Emesis and emetic reflexes initiated from the gut are controlled by the dorsal vagal complex of the brainstem, consisting of the area postrema, the NTS and the DMN. It has long been known that cannabinoids possess antiemetic actions [42, 43•, 44]. Strong evidence supporting a role for CB1 receptors in the dorsal vagal complex mediating these responses was obtained in a number of species [37, 43•, 45]. Furthermore, the presence of the ECS was described in the ferret dorsal vagal complex [37, 43•

Endocannabinoids modulate visceral sensation and pain

Cannabinoids are well known analgesics. Recent studies have revealed new insights into the mechanism of action of cannabinoids and support a role of endocannabinoids in the modulation of visceral pain. Visceral sensitivity recorded in rodents by applying graded colorectal distension is increased in animal models of colitis. Both CB1 and CB2 receptor agonists reduce the visceromotor responses to distension in basal conditions [50]. When hyperalgesia was produced by the instillation of

Endocannabinoids, stress and the GI tract

Accumulating evidence links activation of the corticotrophin releasing factor receptors by their ligands to a number of stress-related changes in GI motor function and alterations in epithelial barrier function [5, 54]. Many of these actions occur peripherally, but there are important central components and a key site of action is in the paraventricular nucleus of the hypothalamus (PVN). Here, it has been shown that CB1 receptors are found on neurons that express corticotrophin releasing factor

Concluding remarks

The ECS is involved in the regulation of gastrointestinal functions and plays important roles in the gut–brain axis. Major progress over the last 5–10 years illustrates that the ECS is involved at both peripheral and central sites, but the relative contributions each make to any given variable, for example food intake, visceral sensation, under physiological or pathophysiological circumstances is not yet fully understood. CB signalling is involved in transmission of sensory events to the brain

Disclosures

MAS has received payment from Sanofi-Synthelabo as a lecturer. KAS has no conflicts of interest to disclose.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank Dr. Joe Davison for critical comments on the manuscript and Winnie Ho for assistance with Figure 1. Original work from the authors’ laboratories is supported by the Deutsche Forschungsgemeinschaft and the Society of Gastroenterology in Bavaria (MAS), the Canadian Institutes of Health Research (KAS) and the Crohn's and Colitis Foundation of Canada (CCFC, KAS). KAS is Alberta Heritage Foundation for Medical Research (AHFMR) Medical Scientist and the CCFC Chair in IBD Research at

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