Muriel Larauche, Agata Mulak, Chrysanthy Ha, Mulugeta Million, Stacy Arnett, Peter Germano, James P Pearson, Mark G Currie, Yvette Taché
{"title":"FAAH 抑制剂 URB597 在 CRF1 激动剂介导的雄性大鼠内脏超敏反应模型中显示出抗超敏作用，并能增加脑和肠道组织脂肪酸酰胺。","authors":"Muriel Larauche, Agata Mulak, Chrysanthy Ha, Mulugeta Million, Stacy Arnett, Peter Germano, James P Pearson, Mark G Currie, Yvette Taché","doi":"10.1111/nmo.14927","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and aims: </strong>The endocannabinoid (eCB) system includes ligands (anandamide and 2-arachidonoyl glycerol, 2-AG), receptors and catabolizing enzymes (fatty acid amide hydrolase, FAAH and monoacylglycerol lipase) expressed in both the brain and gut. We investigated whether the FAAH inhibitor, URB597, influenced visceral pain to colorectal distension (CRD) in an acute stress-related model of visceral hypersensitivity induced by the selective corticotropin-releasing factor receptor subtype 1 (CRF<sub>1</sub>) agonist, cortagine.</p><p><strong>Methods: </strong>Male Sprague-Dawley rats were injected subcutaneously (SC) with URB597 (3 mg/kg) or vehicle and 2 h later, intraperitoneally with cortagine (10 μg/kg) or vehicle. The visceromotor responses (VMR) were assessed to a first CRD (baseline) before injections, and to a second CRD 15 min after the last treatment. Brain, jejunum, and proximal colon were collected from treated and naïve rats for levels quantification of three fatty acid amides (FAAs) [anandamide (arachidonyl-ethanolamide, AEA), oleoyl-ethanolamide (OEA) and palmitoyl-ethanolamide (PEA)], and 2-AG. In separate animals, defecation/diarrhea were monitored after URB597 and cortagine.</p><p><strong>Key results: </strong>URB597 inhibited cortagine-induced increased VMR at 40 mmHg (89.0 ± 14.8% vs. 132.5 ± 15.6% for vehicle SC, p < 0.05) and 60 mmHg (107.5 ± 16.1% vs. 176.9 ± 24.4% for vehicle SC, p < 0.001) while not influencing basal VMR. In URB597 plus cortagine group, FAAs levels increased in the brain and intestinal tissue while 2-AG did not change. URB597 did not modify cortagine-induced defecation/diarrhea versus vehicle.</p><p><strong>Conclusions and inferences: </strong>URB597 shows efficacy to elevate brain and intestinal FAAs and to counteract the colonic hypersensitivity induced by peripheral activation of CRF<sub>1</sub> signaling supporting a potential strategy of FAAH inhibitors to alleviate stress-related visceral hypersensitivity.</p>","PeriodicalId":19123,"journal":{"name":"Neurogastroenterology and Motility","volume":" ","pages":"e14927"},"PeriodicalIF":3.5000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"FAAH inhibitor URB597 shows anti-hyperalgesic action and increases brain and intestinal tissues fatty acid amides in a model of CRF<sub>1</sub> agonist mediated visceral hypersensitivity in male rats.\",\"authors\":\"Muriel Larauche, Agata Mulak, Chrysanthy Ha, Mulugeta Million, Stacy Arnett, Peter Germano, James P Pearson, Mark G Currie, Yvette Taché\",\"doi\":\"10.1111/nmo.14927\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and aims: </strong>The endocannabinoid (eCB) system includes ligands (anandamide and 2-arachidonoyl glycerol, 2-AG), receptors and catabolizing enzymes (fatty acid amide hydrolase, FAAH and monoacylglycerol lipase) expressed in both the brain and gut. We investigated whether the FAAH inhibitor, URB597, influenced visceral pain to colorectal distension (CRD) in an acute stress-related model of visceral hypersensitivity induced by the selective corticotropin-releasing factor receptor subtype 1 (CRF<sub>1</sub>) agonist, cortagine.</p><p><strong>Methods: </strong>Male Sprague-Dawley rats were injected subcutaneously (SC) with URB597 (3 mg/kg) or vehicle and 2 h later, intraperitoneally with cortagine (10 μg/kg) or vehicle. The visceromotor responses (VMR) were assessed to a first CRD (baseline) before injections, and to a second CRD 15 min after the last treatment. Brain, jejunum, and proximal colon were collected from treated and naïve rats for levels quantification of three fatty acid amides (FAAs) [anandamide (arachidonyl-ethanolamide, AEA), oleoyl-ethanolamide (OEA) and palmitoyl-ethanolamide (PEA)], and 2-AG. In separate animals, defecation/diarrhea were monitored after URB597 and cortagine.</p><p><strong>Key results: </strong>URB597 inhibited cortagine-induced increased VMR at 40 mmHg (89.0 ± 14.8% vs. 132.5 ± 15.6% for vehicle SC, p < 0.05) and 60 mmHg (107.5 ± 16.1% vs. 176.9 ± 24.4% for vehicle SC, p < 0.001) while not influencing basal VMR. In URB597 plus cortagine group, FAAs levels increased in the brain and intestinal tissue while 2-AG did not change. 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引用次数: 0
摘要
背景和目的：内源性大麻素（eCB）系统包括配体（anandamide和2-arachidonoyl glycerol，2-AG）、受体和分解酶（脂肪酸酰胺水解酶，FAAH和单酰基甘油脂肪酶），在大脑和肠道中均有表达。我们研究了在选择性促肾上腺皮质激素释放因子受体亚型1（CRF1）激动剂可的松诱导的急性应激相关内脏超敏模型中，FAAH抑制剂URB597是否会影响结肠直肠胀气（CRD）引起的内脏疼痛：雄性 Sprague-Dawley 大鼠皮下注射（SC）URB597（3 毫克/千克）或载体，2 小时后腹腔注射可的松（10 微克/千克）或载体。对注射前的第一次CRD（基线）和最后一次治疗后15分钟的第二次CRD进行内脏运动反应（VMR）评估。从接受治疗的大鼠和未接受治疗的大鼠身上收集大脑、空肠和近端结肠，以定量检测三种脂肪酸酰胺（FAAs）[花生四烯醇乙醇酰胺（anandamide，arachidonyl-ethanolamide，AEA）、油酰乙醇酰胺（OEA）和棕榈酰乙醇酰胺（palmitoyl-ethanolamide，PEA）]和 2-AG 的含量。URB597和可的松作用后，分别监测动物的排便/腹泻情况：主要结果：URB597 抑制了可的松引起的 40 mmHg VMR 增加（89.0 ± 14.8% vs. 132.5 ± 15.6% for vehicle SC, p 结论和推论：URB597具有提高大脑和肠道FAA的功效，并能抵消外周激活CRF1信号诱导的结肠超敏反应，支持FAAH抑制剂缓解应激相关内脏超敏反应的潜在策略。
FAAH inhibitor URB597 shows anti-hyperalgesic action and increases brain and intestinal tissues fatty acid amides in a model of CRF1 agonist mediated visceral hypersensitivity in male rats.
Background and aims: The endocannabinoid (eCB) system includes ligands (anandamide and 2-arachidonoyl glycerol, 2-AG), receptors and catabolizing enzymes (fatty acid amide hydrolase, FAAH and monoacylglycerol lipase) expressed in both the brain and gut. We investigated whether the FAAH inhibitor, URB597, influenced visceral pain to colorectal distension (CRD) in an acute stress-related model of visceral hypersensitivity induced by the selective corticotropin-releasing factor receptor subtype 1 (CRF1) agonist, cortagine.
Methods: Male Sprague-Dawley rats were injected subcutaneously (SC) with URB597 (3 mg/kg) or vehicle and 2 h later, intraperitoneally with cortagine (10 μg/kg) or vehicle. The visceromotor responses (VMR) were assessed to a first CRD (baseline) before injections, and to a second CRD 15 min after the last treatment. Brain, jejunum, and proximal colon were collected from treated and naïve rats for levels quantification of three fatty acid amides (FAAs) [anandamide (arachidonyl-ethanolamide, AEA), oleoyl-ethanolamide (OEA) and palmitoyl-ethanolamide (PEA)], and 2-AG. In separate animals, defecation/diarrhea were monitored after URB597 and cortagine.
Key results: URB597 inhibited cortagine-induced increased VMR at 40 mmHg (89.0 ± 14.8% vs. 132.5 ± 15.6% for vehicle SC, p < 0.05) and 60 mmHg (107.5 ± 16.1% vs. 176.9 ± 24.4% for vehicle SC, p < 0.001) while not influencing basal VMR. In URB597 plus cortagine group, FAAs levels increased in the brain and intestinal tissue while 2-AG did not change. URB597 did not modify cortagine-induced defecation/diarrhea versus vehicle.
Conclusions and inferences: URB597 shows efficacy to elevate brain and intestinal FAAs and to counteract the colonic hypersensitivity induced by peripheral activation of CRF1 signaling supporting a potential strategy of FAAH inhibitors to alleviate stress-related visceral hypersensitivity.
期刊介绍：
Neurogastroenterology & Motility (NMO) is the official Journal of the European Society of Neurogastroenterology & Motility (ESNM) and the American Neurogastroenterology and Motility Society (ANMS). It is edited by James Galligan, Albert Bredenoord, and Stephen Vanner. The editorial and peer review process is independent of the societies affiliated to the journal and publisher: Neither the ANMS, the ESNM or the Publisher have editorial decision-making power. Whenever these are relevant to the content being considered or published, the editors, journal management committee and editorial board declare their interests and affiliations.
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