Cannabinoid (CB₁) receptor activation acts neuronally, reducing GI motility, diarrhoea, pain, transient lower oesophageal sphincter relaxations (TLESRs) and emesis, and promoting eating. CB₂ 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 CB₁ receptors can increase food intake and body weight, exert anti‐emetic activity, reduce gastric acid secretion and TLESRs; CB₂ receptors may have a small role in emesis. Question 1: CB₁ 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 CB₂ receptor function? Intestinal Transit and Secretion. Reduced by endocannabinoids at CB₁ receptors, but not by CB₂ receptor agonists. Q1: Do the effects of endocannabinoids rapidly diminish with repeat‐dosing? Q2: Do CB₂ receptors need to be pathologically upregulated before they are active? Inflammation. CB₁, CB₂ and TRPV1 receptors may mediate an ability of endocannabinoids to reduce GI inflammation or its consequences. Q1: Are CB₂ receptors upregulated by inflammatory or other pathology? Pain. Colonic bacterial flora may upregulate CB₂ receptor expression and thereby increase intestinal sensitivity to noxious stimuli. Q1: Are CB₂ 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.

British Journal of Pharmacology (2007) 152, 663–670. doi:10.1038/sj.bjp.0707422; published online 3 September 2007