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首页> 外文期刊>American Journal of Physiology >Agonists of cannabinoid receptor 1 and 2 inhibit experimental colitis induced by oil of mustard and by dextran sulfate sodium.
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Agonists of cannabinoid receptor 1 and 2 inhibit experimental colitis induced by oil of mustard and by dextran sulfate sodium.

机译：大麻素受体1和2的激动剂抑制芥子油和硫酸葡聚糖钠诱导的实验性结肠炎。

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Oil of mustard (OM) is a potent neuronal activator that is known to elicit visceral hyperalgesia when given intracolonically, but the full extent to which OM is also proinflammatory in the gastrointestinal tract is not known. We have previously shown that male CD-1 mice given a single administration of 0.5% OM develop a severe colitis that is maximum at day 3 and that gradually lessens until essentially absent by day 14. OM-induced neuronal stimulation is reported to be reduced by cannabinoid agonists, and cannabinoid receptor 1 (CB1R)-/- mice have exacerbated experimental colitis. Therefore, we examined the role of cannabinoids in this OM-induced 3-day model of colitis in CD-1 mice and in a 7-day dextran sulfate sodium (DSS) colitis model in BALB/c mice. In OM colitis, the CB1R-selective agonist ACEA and the CB2R-selective agonist JWH-133 reduced (P < 0.05) colon weight gain (means +/- SE; 82 +/- 13% and 47 +/- 15% inhibition, respectively), colon shrinkage (98 +/- 24% and 42 +/- 12%, respectively), colon inflammatory damage score (49 +/- 11% and 40 +/- 12%, respectively), and diarrhea (58 +/- 12% and 43 +/- 11%, respectively). Histological damage was similarly reduced by these treatments. Likewise, CBR agonists attenuated DSS colitis, albeit at higher doses; ACEA at 10 mg/kg, twice daily, inhibited (P < 0.05) macroscopic and microscopic scores (46 +/- 9% and 63 +/- 7%, respectively); whereas 20 mg/kg, twice daily, of JWH-133 was required to diminish (P < 0.05) macroscopic and microscopic scores (29 +/- 7% and 43 +/- 5%, respectively). CB1R and CB2R immunostaining of colon sections revealed that CB1R in enteric neurons was more intense in colitic vs. control mice; however, CB1R was also increased in the endothelial layer in OM colitis only. CB2R immunostaining was more marked in infiltrated immune cells in OM colitis. These findings validate the OM colitis model with respect to the DSS model and provide strong support to the emerging idea that cannabinoid receptor activation mediates protective mechanisms in experimental colitis. The demonstration of CB1R agonist effects in colitis support the neurogenic nature of the OM-induced colitis model and reinforce the importance of neuronal activation in intestinal inflammation.
机译：芥末油（OM）是一种有效的神经元激活剂，已知在结肠内给药时会引起内脏痛觉过敏，但尚不了解OM在胃肠道中是否具有促炎作用。我们以前已经证明，单次施用0.5％OM的雄性CD-1小鼠会发展成严重的结肠炎，这种结肠炎在第3天最大，并且逐渐减轻，直到第14天基本上消失。大麻素激动剂和大麻素受体1（CB1R）-/-小鼠加剧了实验性结肠炎。因此，我们检查了大麻素在此OM诱导的CD-1小鼠结肠炎3天模型和BALB / c小鼠7天硫酸葡聚糖硫酸钠（DSS）结肠炎模型中的作用。在OM结肠炎中，CB1R选择性激动剂ACEA和CB2R选择性激动剂JWH-133降低了（P <0.05）结肠增重（平均+/- SE; 82 +/- 13％和47 +/- 15％抑制， ），结肠收缩（分别为98 +/- 24％和42 +/- 12％），结肠炎性损害评分（分别为49 +/- 11％和40 +/- 12％）和腹泻（58 + /-分别为12％和43 +/- 11％）。这些治疗同样减少了组织学损伤。同样，CBR激动剂可减轻DSS结肠炎，尽管剂量较高。 10 mg / kg的ACEA，每日两次，抑制（P <0.05）宏观和微观得分（分别为46 +/- 9％和63 +/- 7％）;而每天两次两次服用20 mg / kg的JWH-133则要降低（P <0.05）宏观和微观得分（分别为29 +/- 7％和43 +/- 5％）。结肠切片的CB1R和CB2R免疫染色显示，与对照小鼠相比，肠溶性神经元中肠神经元中的CB1R更为强烈。然而，仅在OM结肠炎中，内皮层中的CB1R也增加了。 CB2R免疫染色在OM结肠炎的浸润免疫细胞中更为明显。这些发现验证了相对于DSS模型的OM结肠炎模型，并为大麻素受体激活介导实验性结肠炎的保护机制这一新兴观点提供了有力的支持。 CB1R激动剂在结肠炎中的作用证明支持OM诱导的结肠炎模型的神经源性，并增强了神经元激活在肠道炎症中的重要性。

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