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首页> 外文期刊>Pain. >Vagal anandamide signaling via cannabinoid receptor 1 contributes to luminal 5-HT modulation of visceral nociception in rats
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Vagal anandamide signaling via cannabinoid receptor 1 contributes to luminal 5-HT modulation of visceral nociception in rats

机译：大麻素受体1引起的迷走性anandamide信号传导促进大鼠内脏伤害感受的腔内5-HT调节

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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-HT 3R-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.
机译：5-羟色胺（5-HT）在感染后肠易激综合征（PI-IBS）的发病机理中起关键作用，而腔内5-HT依赖于时间调节内脏伤害感受。我们发现，来自PI-IBS患者的十二指肠活检显示5-HT升高，而anandamide水平降低，而anandamide降低与腹痛严重程度相关，这表明PI-IBS中5-HT和内源性大麻素信号通路之间存在联系。为了理解这一点，我们研究了内源性大麻素在大鼠模型中5-HT调节内脏伤害感受中的作用。急性十二指肠内应用5-HT减弱了对大肠扩张的内脏运动反应（VMR），而大麻素受体1（CB1）拮抗剂AM251逆转了这种反应。腔内5-HT处理后十二指肠腺烷酰胺（但不是2-花生四烯酰基甘油）的含量大大增加。 5-HT 3受体（5-HT3R）拮抗剂Granisetron消除了这种作用，该物质被夜光递送至优先靶向迷走神经末端。迷走神经传入神经的化学去神经阻滞了5-HT诱发的抗伤害感受和anandamide的释放。慢性腔内5-HT暴露5天增加了基线VMR和5HT后的VMR（第4天和第5天）。从第1天到第5天，十二指肠中的anandamide和N-酰基磷脂酰乙醇胺特异性磷脂酶D（NAPE-PLD，anandamide合成酶）蛋白逐渐下降。每天的Granisetron预处理消除了5-HT的时间依赖性作用。从第3天开始每天使用CB1激动剂或anandamide进行预处理，可减轻5-HT引起的痛觉过敏。这些数据表明迷走神经5-HT 3R介导的十二指肠anandamide释放通过CB1信号促成急性管腔5-HT诱导的抗伤害感受，而减少的anandamide与慢性5-HT治疗后的痛觉过敏相关。对周围迷走神经七烷酰胺信号传导的进一步理解可以提供对5-HT相关IBS潜在机制的了解。

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