Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China Department of pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, China.
Pain. 2014 Aug;155(8):1591-1604. doi: 10.1016/j.pain.2014.05.005. Epub 2014 May 9.
Serotonin (5-HT) plays pivotal roles in the pathogenesis of postinfectious irritable bowel syndrome (PI-IBS), and luminal 5-HT time-dependently modulates visceral nociception. We found that duodenal biopsies from PI-IBS patients exhibited increased 5-HT and decreased anandamide levels and that decreased anandamide was associated with abdominal pain severity, indicating a link between 5-HT and endocannabinoid signaling pathways in PI-IBS. To understand this, we investigated the role of endocannabinoids in 5-HT modulation of visceral nociception in a rat model. Acute intraduodenally applied 5-HT attenuated the visceromotor response (VMR) to colorectal distention, and this was reversed by the cannabinoid receptor 1 (CB1) antagonist AM251. Duodenal anandamide (but not 2-arachidonoylglycerol) content was greatly increased after luminal 5-HT treatment. This effect was abrogated by the 5-HT 3 receptor (5-HT3R) antagonist granisetron, which was luminally delivered to preferentially target vagal terminals. Chemical denervation of vagal afferents blocked 5-HT-evoked antinociception and anandamide release. Chronic luminal 5-HT exposure for 5 days increased baseline VMR and VMR post-5-HT (days 4 and 5). Duodenal levels of anandamide and N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD, the anandamide-synthesizing enzyme) protein gradually declined from day 1 to 5. The time-dependent effects of 5-HT were abolished by daily granisetron pretreatment. Daily pretreatment with CB1 agonists or anandamide from day 3 attenuated 5-HT-induced hyperalgesia. These data suggest that vagal 5-HT3R-mediated duodenal anandamide release contributes to acute luminal 5-HT-induced antinociception via CB1 signaling, whereas decreased anandamide is associated with hyperalgesia upon chronic 5-HT treatment. Further understanding of peripheral vagal anandamide signaling may provide insights into the mechanisms underlying 5-HT-related IBS.
5-羟色胺（5-HT）在感染后肠易激综合征（PI-IBS）的发病机制中起关键作用，腔内分泌的 5-HT 可随时间调节内脏痛觉。我们发现 PI-IBS 患者的十二指肠活检显示 5-HT 水平升高，而大麻素受体 1（CB1）拮抗剂 AM251 可逆转这一现象。此外，大麻素受体 1（CB1）拮抗剂 AM251 还可逆转这种降低，表明 5-HT 和内源性大麻素信号通路之间存在联系。为了了解这一点，我们在大鼠模型中研究了内源性大麻素在 5-HT 调节内脏痛觉中的作用。急性十二指肠内给予 5-HT 可减弱结直肠扩张引起的内脏运动反应（VMR），而这种作用可被大麻素受体 1（CB1）拮抗剂 AM251 逆转。5-HT 处理后，十二指肠中的花生四烯酸（但不是 2-花生四烯酰甘油）含量大大增加。这种作用被腔内给予的 5-HT3 受体（5-HT3R）拮抗剂 granisetron 阻断，而 granisetron 主要作用于迷走神经末梢。迷走神经传入纤维的化学去神经支配阻断了 5-HT 诱导的抗伤害作用和花生四烯酸的释放。5 天的慢性腔内 5-HT 暴露增加了基础 VMR 和 5-HT 后 VMR（第 4 和第 5 天）。十二指肠中花生四烯酸和 N-酰基磷酰乙醇胺特异性磷脂酶 D（NAPE-PLD，花生四烯酸合成酶）蛋白水平从第 1 天到第 5 天逐渐下降。5-HT 的时间依赖性作用被每日 granisetron 预处理所消除。从第 3 天开始，每日给予 CB1 激动剂或花生四烯酸预处理可减轻 5-HT 引起的痛觉过敏。这些数据表明，迷走神经 5-HT3R 介导的十二指肠花生四烯酸释放通过 CB1 信号参与急性腔内 5-HT 诱导的抗伤害作用，而慢性 5-HT 处理后花生四烯酸的减少与痛觉过敏有关。进一步了解外周迷走神经内源性大麻素信号可能有助于深入了解 5-HT 相关 IBS 的发病机制。
