Cannabinoid Mechanisms in Human Gastrointestinal Motor and Sensory Functions

人类胃肠运动和感觉功能中的大麻素机制

• 批准号: 7713946
• 负责人: MICHAEL L. CAMILLERI
• 金额: $ 37.59万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7713946
• 关键词: 2-arachidonylglycerol; Abdominal Pain; Acceleration; Address; Affect; Agonist; Antral; Body Weight decreased; Brain Stem; CNR1 gene; Cannabinoids; Cholinesterase Inhibitors; Clinical; Colon; Databases; Desire for food; Development; Diarrhea; Disease; Dose; Drug usage; Endocannabinoids; Enzymes; Esthesia; Functional disorder; Gastric Emptying; Gastrointestinal Transit; Gastrointestinal tract structure; Genes; Genetic Variation; Genotype; Health; Human; Hydrolase Gene; Inflammation; Inflammatory; Intestines; Irritable Bowel Syndrome; Lipids; Lymphocyte; Marijuana; Measures; Mediating; Medical; Medicine; Metabolism; Monoacylglycerol Lipases; Motor; Muscarinics; Neostigmine; Nerve Pain; Nociception; Obesity; Pain; Participant; Patients; Pharmaceutical Preparations; Placebos; Population; Proline; Proteins; Satiation; Sensory; Single Nucleotide Polymorphism; Stomach; Symptoms; T-Lymphocyte; Tetrahydrocannabinol; Threonine; Variant; Work; anandamide; base; cannabinoid receptor; cell motility; cholinergic; cholinergic neuron; fatty acid amide hydrolase; gastrointestinal; in vivo; obesity treatment; protein expression; public health relevance; receptor; research study; response; rimonabant

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.

描述（由申请人提供）：肠易激综合征（IBS）影响美国人群的15％。尽管越来越了解IBS的病理生理学，但仍未满足的临床需求，没有批准有效的药物来治疗与IBS相关的腹痛。大麻素受体（CBR）在脑干，胃和结肠中的胆碱能神经元上。 CB1拮抗剂Rimonabant可有效诱导体重减轻。但是，这种好处的机制尚不清楚。该实验室的人类研究表明，CBR激动剂Dronabinol抑制了胃和结肠运动，这可能会改变肥胖症的食欲或饱腹感，并且可能在治疗IBS方面具有潜力。该提案的重点是阐明在健康和IBS中，大麻素受体（CBR）对胃和结肠运动的调节以及感觉功能的机制。 CB1受体还参与了伤害感受和介导炎症，这些炎症越来越被认为是IBS中潜在的病理生理机制。有内源性大麻素（或内源性大麻素），例如anandamide和2-芳烃甘油。 Anandamide在体内被脂肪酸酰胺水解酶（FAAH）灭活。人FAAH基因中的单个核苷酸多态性（SNP）以纯合形式（385c至a），以纯合形式将FAAH中保守的脯氨酸残基转换为苏氨酸（p129t），并降低了FAAH蛋白的表达。目前尚不清楚此SNP是否影响对大麻素的反应。一般的长期目的是了解大麻素机制调节对胃肠道运动，感觉和炎症活性的影响，这是开发IBS治疗方法的前奏。当前建议的目的是：首先，确定CB受体调节是否影响对标准餐和胃肠道转运的鼻响应反应，并评估毒蕈碱胆碱能机制与CB调节的相互作用；其次，要比较两种剂量的大麻素激动剂，dronabinol（5和10 mg/day）和安慰剂对腹泻 - 主导IBS（D-IBS）中胃肠道和结肠运动以及感觉功能的影响；第三，检查FAAH基因和MGLL基因的变化（对于限制酶，单酰甘油脂肪酶，对于另一种内源性大麻素，2-羟基二酰基甘油）是否会影响大麻蛋白调节对胃肠道运动和感官功能的药理作用；第四，确定FAAH（C385a）遗传变异对胃肠道和结肠过渡对龙纳比醇的影响。这项研究将为开发大麻素治疗的常见胃肠道疾病提供基础。它还将增强对可能与胃功能控制和肥胖治疗相关的CBR调制潜在影响的理解。公共卫生相关性：肠易激综合症（IBS）影响约15％的美国人群。仍然没有批准有效且安全的药物来治疗与IBS中肠症状相关的腹痛。该建议是研究对胃肠道和疼痛神经中存在的同一信使的药用大麻或合成药物的反应的身体使者（受体）的影响。这些行动可能与为IBS开发新疗法有关。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。