Endocannabinoids and the gastrointestinal tract: What are the key questions?

Abstract

Cannabinoid (CB 1) receptor activation acts neuronally, reducing GI motility, diarrhoea, pain, transient lower oesophageal sphincter relaxations (TLESRs) and emesis, and promoting eating. CB 2 receptor activation acts mostly via immune cells to reduce inflammation. What are the key questions which now need answering to further understand endocannabinoid pathophysiology? GPR55. Does this receptor have a GI role? Satiety, Nausea, Vomiting, Gastro-Oesophageal Reflux, Gastric Emptying. Endocannabinoids acting at CB 1 receptors can increase food intake and body weight, exert anti-emetic activity, reduce gastric acid secretion and TLESRs; CB 2 receptors may have a small role in emesis. Question 1: CB 1 receptor activation reduces emesis and gastric emptying but the latter is associated with nausea. How is the paradox explained? Q2: Do non-CB receptor actions of endocannabinoids (for example TRPV1) also modulate emesis? Q3: Is pathology necessary (gastritis, gastro-oesophageal reflux) to observe CB 2 receptor function? Intestinal Transit and Secretion. Reduced by endocannabinoids at CB 1 receptors, but not by CB 2 receptor agonists. Q1: Do the effects of endocannabinoids rapidly diminish with repeat-dosing? Q2: Do CB 2 receptors need to be pathologically upregulated before they are active? Inflammation. CB 1, CB 2 and TRPV1 receptors may mediate an ability of endocannabinoids to reduce GI inflammation or its consequences. Q1: Are CB 2 receptors upregulated by inflammatory or other pathology? Pain. Colonic bacterial flora may upregulate CB 2 receptor expression and thereby increase intestinal sensitivity to noxious stimuli. Q1: Are CB 2 receptors the interface between colonic bacteria and enteric- or extrinsic nerve sensitivity? Relevance of endocannabinoids to humans. Perhaps apart from appetite, this is largely unknown. © 2007 Nature Publishing Group All rights reserved.