School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
Division of Biomedical Sciences, St George's University of London, London, UK.
Neuropeptides. 2017 Oct;65:28-36. doi: 10.1016/j.npep.2017.04.006. Epub 2017 Apr 21.
Glucagon-like peptide-1 (GLP-1) receptor agonists are indicated for the treatment of Type 2 diabetes and obesity, but can cause nausea and emesis in some patients. GLP-1 receptors are distributed widely in the brain, where they contribute to mechanisms of emesis, reduced appetite and aversion, but it is not known if these centrally located receptors also contribute to a modulation of gastric slow wave activity, which is linked causally to nausea. Our aim was to investigate the potential of the GLP-1 receptor agonist, exendin-4, administered into the 3rd ventricle to modulate emesis, feeding and gastric slow wave activity. Thermoregulation and cardiovascular parameters were also monitored, as they are disturbed during nausea. Ferrets were used as common laboratory rodents do not have an emetic reflex. A guide cannula was implanted into the 3rd ventricle for delivering a previously established dose of exendin-4 (10nmol), which had been shown to induce emesis and behaviours indicative of 'nausea'. Radiotelemetry recorded gastric myoelectric activity (GMA; slow waves), blood pressure and heart rate variability (HRV), and core temperature; food intake and behaviour were also assessed. Exendin-4 (10nmol, i.c.v.) decreased the dominant frequency of GMA, with an associated increase in the percentage of bradygastric power (lasting ~4h). Food intake was inhibited in all animals, with 63% exhibiting emesis. Exendin-4 also increased blood pressure (lasting ~24h) and heart rate (lasting ~7h), decreased HRV (lasting ~24h), and caused transient hyperthermia. None of the above parameters were emesis-dependent. The present study shows for the first time that gastric slow waves may be modulated by GLP-1 receptors in the brain through mechanisms that appear independent from emesis. Taken together with a reduction in HRV, the findings are consistent with changes associated with the occurrence of nausea in humans.
胰高血糖素样肽-1（GLP-1）受体激动剂被用于治疗 2 型糖尿病和肥胖症，但会引起一些患者恶心和呕吐。GLP-1 受体广泛分布于大脑中，在那里它们有助于呕吐、食欲减退和厌恶的机制，但目前尚不清楚这些位于中枢的受体是否也有助于调节与恶心有关的胃慢波活动。我们的目的是研究 GLP-1 受体激动剂 exendin-4 给药于第三脑室是否能调节呕吐、摄食和胃慢波活动。还监测了体温调节和心血管参数，因为它们在恶心期间会受到干扰。使用雪貂作为常见的实验室啮齿动物，因为它们没有呕吐反射。将引导套管植入第三脑室，以给予先前建立的 exendin-4 剂量（10nmol），该剂量已被证明可引起呕吐和“恶心”行为。无线电遥测记录胃肌电活动（GMA；慢波）、血压和心率变异性（HRV）以及核心体温；还评估了食物摄入和行为。脑室内给予 exendin-4（10nmol）可降低 GMA 的主导频率，同时伴慢波功率的百分比较高（持续约 4 小时）。所有动物的食物摄入均受到抑制，有 63%的动物出现呕吐。Exendin-4 还可升高血压（持续约 24 小时）和心率（持续约 7 小时），降低 HRV（持续约 24 小时），并导致短暂的体温升高。上述参数均与呕吐无关。本研究首次表明，通过与呕吐无关的机制，大脑中的 GLP-1 受体可能调节胃慢波。与 HRV 减少一起，这些发现与人类恶心发生时相关的变化一致。
