Vera Gema, López-Pérez Ana E, Uranga José A, Girón Rocío, Martín-Fontelles Ma Isabel, Abalo Raquel
Área de Farmacología y Nutrición, Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan CarlosAlcorcón, Spain; Unidad Asociada I+D+i del Instituto de Química Médica, Consejo Superior de Investigaciones CientíficasMadrid, Spain; Unidad Asociada I+D+i del Instituto de Investigación en Ciencias de la Alimentación, Consejo Superior de Investigaciones CientíficasMadrid, Spain; Grupo de Excelencia Investigadora URJC-Banco de Santander-Grupo Multidisciplinar de Investigación y Tratamiento del Dolor (i+DOL)Alcorcón, Spain.
Grupo de Excelencia Investigadora URJC-Banco de Santander-Grupo Multidisciplinar de Investigación y Tratamiento del Dolor (i+DOL)Alcorcón, Spain; Unidad del Dolor, Servicio de Anestesia, Hospital General Universitario Gregorio MarañónMadrid, Spain.
Front Pharmacol. 2017 Feb 6;8:37. doi: 10.3389/fphar.2017.00037. eCollection 2017.
In different models of paralytic ileus, cannabinoid receptors are overexpressed and endogenous cannabinoids are massively released, contributing to gastrointestinal dysmotility. The antitumoral drug vincristine depresses gastrointestinal motility and a similar mechanism could participate in this effect. Therefore, our aim was to determine, using CB and CB antagonists, whether an increased endocannabinoid tone is involved in vincristine-induced gastrointestinal ileus. First, we confirmed the effects of vincristine on the gut mucosa, by conventional histological techniques, and characterized its effects on motility, by radiographic means. Conscious male Wistar rats received an intraperitoneal injection of vincristine (0.1-0.5 mg/kg), and barium sulfate (2.5 ml; 2 g/ml) was intragastrically administered 0, 24, or 48 h later. Serial X-rays were obtained at different time-points (0-8 h) after contrast. X-rays were used to build motility curves for each gastrointestinal region and determine the size of stomach and caecum. Tissue samples were taken for histology 48 h after saline or vincristine (0.5 mg/kg). Second, AM251 (a CB receptor antagonist) and AM630 (a CB receptor antagonist) were used to determine if CB and/or CB receptors are involved in vincristine-induced gastrointestinal dysmotility. Vincristine induced damage to the mucosa of ileum and colon and reduced gastrointestinal motor function at 0.5 mg/kg. The effect on motor function was particularly evident when the study started 24 h after administration. AM251, but not AM630, significantly prevented vincristine effect, particularly in the small intestine, when administered thrice. AM251 alone did not significantly alter gastrointestinal motility. The fact that AM251, but not AM630, is capable of reducing the effect of vincristine suggests that, like in other experimental models of paralytic ileus, an increased cannabinoid tone develops and is at least partially responsible for the alterations induced by the antitumoral drug on gastrointestinal motor function. Thus, CB antagonists might be useful to prevent/treat ileus induced by vincristine.
在不同的麻痹性肠梗阻模型中，大麻素受体过度表达，内源性大麻素大量释放，导致胃肠动力障碍。抗肿瘤药物长春新碱会抑制胃肠蠕动，可能存在类似机制参与这一效应。因此，我们的目的是使用大麻素（CB）和CB拮抗剂来确定内源性大麻素水平升高是否与长春新碱诱导的胃肠麻痹有关。首先，我们通过传统组织学技术证实了长春新碱对肠黏膜的影响，并通过影像学手段表征了其对胃肠动力的影响。清醒的雄性Wistar大鼠腹腔注射长春新碱（0.1 - 0.5mg/kg），并在0、24或48小时后胃内给予硫酸钡（2.5ml；2g/ml）。在造影后的不同时间点（0 - 8小时）获取系列X射线。X射线用于构建每个胃肠区域的动力曲线，并确定胃和盲肠的大小。在给予生理盐水或长春新碱（0.5mg/kg）48小时后采集组织样本进行组织学检查。其次，使用AM251（一种CB受体拮抗剂）和AM630（一种CB受体拮抗剂）来确定CB1和/或CB2受体是否参与长春新碱诱导的胃肠动力障碍。长春新碱在0.5mg/kg时会导致回肠和结肠黏膜损伤，并降低胃肠运动功能。当在给药后24小时开始研究时，对运动功能的影响尤为明显。AM251（而非AM630）三次给药时可显著预防长春新碱的作用，尤其是在小肠。单独使用AM251不会显著改变胃肠蠕动。AM251而非AM630能够减轻长春新碱的作用，这一事实表明，与其他麻痹性肠梗阻实验模型一样，大麻素水平升高，并且至少部分地导致了抗肿瘤药物对胃肠运动功能的改变。因此，CB拮抗剂可能有助于预防/治疗长春新碱诱导的肠梗阻。
