Cannabinoid Mechanisms in Human Gastrointestinal Motor and Sensory Functions

描述(申请人提供)：肠易激综合征(IBS)影响大约15%的美国人口。尽管人们对IBS的病理生理学有了越来越多的了解，但仍有一些临床需求没有得到满足，也没有有效的药物被批准用于治疗与IBS相关的腹痛。大麻素受体(CBR)位于脑干、胃和结肠的胆碱能神经元上。CB1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激动剂屈诺比诺可以抑制胃和结肠的运动，这可能会改变肥胖者的食欲或饱腹感，并可能在治疗IBS方面具有潜力。这项建议侧重于阐明在健康和IBS中大麻素受体(CBR)调节胃和结肠运动和感觉功能的机制。CB1受体还参与伤害性感受和介导炎症反应，被认为是IBS潜在的病理生理机制。有内源性大麻素(或内源性大麻素)，如双胺和2-花生四烯基甘油。阿南达胺在体内被脂肪酸酰胺水解酶(FAAH)灭活。人类FAAH基因(385C到A)的单核苷酸多态性(SNP)以纯合子的形式将FAAH中保守的脯氨酸残基转化为苏氨酸(P129T)，并降低FAAH蛋白的表达。目前尚不清楚这种SNP是否会影响对大麻素的反应。总的长期目标是了解大麻素机制对胃肠运动、感觉和炎症活动的调节作用，作为开发IBS治疗方法的前奏。目前这项建议的目的是：第一，确定CB受体调节是否影响对标准膳食和胃肠道转运的胃窦运动反应，并评估毒碱胆碱能机制与CB调节的相互作用；第二，比较两种剂量的大麻类激动剂--屈诺麻酚(5 mg/天和10 mg/天)和安慰剂对腹泻型IBS(D-IBS)胃肠和结肠运动和感觉功能的影响；第三，检测FAAH基因和MGLL基因(另一种限速酶，单酰甘油脂肪酶)的变异是否影响大麻类化合物调节胃肠运动和感觉功能的药理作用；第四，确定FAAH(C385A)基因变异对屈诺比诺的胃肠和结肠转运反应的影响。本研究将为大麻素类药物治疗常见胃肠道疾病的发展提供依据。这也将加强对CBR调节的潜在影响的理解，这可能与控制胃功能和治疗肥胖有关。公共卫生相关性：肠易激综合征(IBS)影响了大约15%的美国人口。目前还没有有效和安全的药物被批准用于治疗IBS中与肠道症状相关的腹痛。这项建议是为了研究身体信使(受体)对药用大麻或合成药物的影响，这些药物作用于胃肠道和疼痛神经中的相同信使。这些行动可能与开发治疗IBS的新方法有关。这些研究还将进一步了解医用大麻等药物对胃功能的潜在影响，这些药物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.