Cannabinoid Mechanisms in Human Gastrointestinal Motor and Sensory Functions

描述（由申请人提供）：肠易激综合征（IBS）影响约15%的美国人口。尽管对IBS的病理生理学的理解不断增加，但仍存在未满足的临床需求，并且没有批准用于治疗与IBS相关的腹痛的有效药物。大麻素受体（CBR）位于脑干、胃和结肠中的胆碱能神经元上。CB 1拮抗剂利莫那班在诱导体重减轻方面是有效的;然而，这种益处的机制尚不清楚。该实验室的人体研究表明，CBR激动剂屈大麻酚抑制胃和结肠运动，这可能会改变肥胖症患者的食欲或饱足感，并可能在治疗IBS方面具有潜力。该提案的重点是阐明大麻素受体（CBR）在健康和IBS中调节胃和结肠运动和感觉功能的机制。CB 1受体还参与伤害感受和介导炎症，这被越来越多地认为是IBS的潜在病理生理机制。有内源性大麻素（或内源性大麻素），如大麻素和2-花生四烯甘油。大麻素在体内被脂肪酸酰胺水解酶（FAAH）灭活。人FAAH基因中的单核苷酸多态性（SNP）（385 C至A）以纯合形式将FAAH中的保守脯氨酸残基转化为苏氨酸（P129 T），并降低FAAH蛋白表达。目前还不清楚这种SNP是否会影响对大麻素的反应。一般的长期目标是了解大麻素机制对GI运动，感觉和炎症活动的调节作用，作为开发IBS治疗方法的前奏。本研究的目的是：第一，确定CB受体调节是否影响胃窦运动对标准餐和胃肠传输的反应，并评估毒蕈碱胆碱能机制与CB调节的相互作用;第二，为了比较两种剂量的大麻素激动剂的效果，屈大麻酚（5和10 mg/天）和安慰剂对腹泻型IBS（D-IBS）的胃肠道和结肠运动和感觉功能的影响;第三，检测FAAH基因和MGLL基因的变异是否（对于限速酶，单酰基甘油脂酶，对于另一种内源性大麻素，2-花生四烯酸甘油）影响大麻素调节对胃肠运动和感觉功能的药理学作用;第四，确定FAAH（C385 A）基因变异对屈大麻酚胃肠道和结肠转运反应的影响。本研究将为大麻素治疗常见胃肠道疾病的发展提供依据。它还将增强对CBR调节的潜在影响的理解，这可能与胃功能的控制和肥胖的治疗有关。肠易激综合征（IBS）影响约15%的美国人口。目前仍没有有效和安全的药物被批准用于治疗IBS患者与肠道症状相关的腹痛。这项建议是研究对药用大麻或合成药物产生反应的身体信使（受体）的影响，这些药物对胃肠道和疼痛神经中存在的相同信使起作用。这些行动可能与开发IBS的新治疗方法有关。这些研究还将进一步了解医用大麻等药物对胃功能的潜力，这可能与食欲控制有关。

DESCRIPTION (provided by applicant): 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.