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

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.