Irritable bowel syndrome (IBS) affects about 15% of the U.S. population. Despite increasing understanding of the pathophysiology of IBS, there are unmet clinical needs and no effective medication approved for the treatment of abdominal pain associated with IBS. Cannabinoid receptors (CBR) are on cholinergic neurons in the brain stem, stomach and colon. A CB1 antagonist, rimonabant, is effective in induction of weight loss; however, the mechanism of this benefit is unclear. Human studies from this lab show that a CBR agonist, dronabinol, inhibits gastric and colonic motility, which may alter appetite or satiation in obesity, and may have potential in the treatment of IBS. This proposal focuses on clarifying the mechanisms involved in the modulation of gastric and colonic motor and sensory functions by cannabinoid receptors (CBR) in health and in IBS. CB1 receptors are also involved in nociception and in mediating inflammation which are increasingly recognized as being potential pathophysiological mechanisms in IBS. There are endogenous cannabinoids (or endocannabinoids) such as anandamide and 2-arachidonyl glycerol. Anandamide is inactivated by a fatty acid amide hydrolase (FAAH) in vivo. A single nucleotide polymorphism (SNP) in the human FAAH gene (385C to A), in homozygous form, converts a conserved proline residue in FAAH to threonine (P129T), and reduces FAAH protein expression. It is unclear whether this SNP influences responses to cannabinoids. The general long-term aim is to understand the effect of modulation of cannabinoid mechanisms on GI motor, sensory and inflammatory activity as a prelude to developing treatments for IBS. The aims of the current proposal are: First, to determine whether CB receptor modulation influences the antral motor response to a standard meal and gastrointestinal transit and to evaluate the interaction of muscarinic cholinergic mechanisms with CB modulation; second, to compare the effects of two doses of the cannabinoid agonist, dronabinol (5 and 10 mg/day) and placebo on gastrointestinal and colonic motor and sensory functions in diarrhea-predominant IBS (D-IBS); third, to examine whether variations in the FAAH gene and the MGLL gene (for the rate limiting enzyme, monoacylglycerol lipase, for another endocannabinoid, 2-arachidonyl glycerol) influence the pharmacological effect of cannabinoid modulation on gastrointestinal motor and sensory functions; and fourth, to determine the effect of genetic variation in FAAH (C385A) on gastrointestinal and colonic transit response to dronabinol. This study will provide the basis for the development of cannabinoid therapy of common GI diseases. It will also enhance understanding of the potential effects of CBR modulation that may be relevant to the control of gastric function and the treatment of obesity. PUBLIC HEALTH RELEVANCE: Irritable bowel syndrome (IBS) affects about 15% of the U.S. population. There are still no effective and safe medications approved for the treatment of abdominal pain associated with bowel symptoms in IBS. This proposal is to study the effects of the body messengers (receptors) that respond to medicinal marijuana or synthetic medicines that work on the same messengers that are present in the gastrointestinal tract and pain nerves. These actions may be relevant to develop new treatments for IBS. The studies will also provide further understanding of the potential of medications like medical marijuana on stomach function that may be relevant to appetite control.