Department of Psychology, School of Art and Science, University of Pennsylvania, Philadelphia, PA 19104, USA.
Neuropharmacology. 2012 Apr;62(5-6):1916-27. doi: 10.1016/j.neuropharm.2011.12.022. Epub 2011 Dec 28.
The FDA-approved glucagon-like-peptide-1 receptor (GLP-1R) agonists exendin-4 and liraglutide reduce food intake and body weight. Nausea is the most common adverse side effect reported with these GLP-1R agonists. Whether food intake suppression by exendin-4 and liraglutide occurs independently of nausea is unknown. Further, the neurophysiological mechanisms mediating the nausea associated with peripheral GLP-1R agonist use are poorly understood. Using two established rodent models of nausea [conditioned taste avoidance (CTA) and pica (ingestion of nonnutritive substances)], results show that all peripheral doses of exendin-4 that suppress food intake also produce CTA, whereas one dose of liraglutide suppresses intake without producing CTA. Chronic (12 days) daily peripheral administration of exendin-4 produces a progressive increase in pica coupled with stable, sustained food intake and body weight suppression, whereas the pica response and food intake reduction by daily liraglutide are more transient. Results demonstrate that the nausea response accompanying peripheral exendin-4 occurs via a vagal-independent pathway involving GLP-1R activation in the brain as the exendin-4-induced pica response is attenuated with CNS co-administration of the GLP-1R antagonist exendin-(9-39), but not by vagotomy. Direct administration of exendin-4 to the medial subnucleus of the nucleus tractus solitarius (mNTS), but not to the central nucleus of the amygdala, reduced food intake and produced a pica response, establishing the mNTS as a potential GLP-1R-expressing site mediating nausea responses associated with GLP-1R agonists.
美国食品和药物管理局批准的胰高血糖素样肽-1 受体（GLP-1R）激动剂 exendin-4 和利拉鲁肽可减少食物摄入和体重。这些 GLP-1R 激动剂最常见的不良反应是恶心。尚不清楚 exendin-4 和利拉鲁肽抑制食欲是否独立于恶心发生。此外，介导外周 GLP-1R 激动剂使用相关恶心的神经生理机制知之甚少。使用两种已建立的恶心啮齿动物模型[条件味觉回避（CTA）和异食癖（摄入非营养物质）]，结果表明，抑制食欲的 exendin-4 的所有外周剂量均产生 CTA，而利拉鲁肽的一个剂量抑制摄入而不产生 CTA。慢性（12 天）每日外周给予 exendin-4 会导致异食癖逐渐增加，同时伴有稳定持续的食物摄入和体重减轻，而每日给予利拉鲁肽的异食癖反应和食物摄入减少则更为短暂。结果表明，外周给予 exendin-4 时伴随的恶心反应是通过一种不依赖于迷走神经的途径发生的，该途径涉及大脑中的 GLP-1R 激活，因为 exendin-4 诱导的异食癖反应可通过中枢给予 GLP-1R 拮抗剂 exendin-（9-39）减弱，但迷走神经切断术不能减弱。直接向孤束核内侧亚核（mNTS）给予 exendin-4 而不是向杏仁核中央核给予 exendin-4 可减少食物摄入并产生异食癖反应，这表明 mNTS 可能是介导与 GLP-1R 激动剂相关的恶心反应的 GLP-1R 表达部位。
