Department Internal Medicine, Division Gastroenterology, University of Michigan Medical Center, Ann Arbor, MI, United States.
Pain. 2018 Sep;159(9):1777-1789. doi: 10.1097/j.pain.0000000000001271.
In humans, chronic psychological stress is associated with increased intestinal paracellular permeability and visceral hyperalgesia, which is recapitulated in the chronic intermittent water avoidance stress (WAS) rat model. However, it is unknown whether enhanced visceral pain and permeability are intrinsically linked and correlate. Treatment of rats with lubiprostone during WAS significantly reduced WAS-induced changes in intestinal epithelial paracellular permeability and visceral hyperalgesia in a subpopulation of rats. Lubiprostone also prevented WAS-induced decreases in the epithelial tight junction protein, occludin (Ocln). To address the question of whether the magnitude of visceral pain correlates with the extent of altered intestinal permeability, we measured both end points in the same animal because of well-described individual differences in pain response. Our studies demonstrate that visceral pain and increased colon permeability positively correlate (0.6008, P = 0.0084). Finally, exposure of the distal colon in control animals to Ocln siRNA in vivo revealed that knockdown of Ocln protein inversely correlated with increased paracellular permeability and enhanced visceral pain similar to the levels observed in WAS-responsive rats. These data support that Ocln plays a potentially significant role in the development of stress-induced increased colon permeability. We believe this is the first demonstration that the level of chronic stress-associated visceral hyperalgesia directly correlates with the magnitude of altered colon epithelial paracellular permeability.
在人类中，慢性心理应激与肠道上皮细胞旁通透性增加和内脏痛觉过敏有关，这在慢性间歇性水回避应激（WAS）大鼠模型中得到了重现。然而，尚不清楚增强的内脏疼痛和通透性是否内在相关和相关。在 WAS 期间用鲁比前列酮治疗大鼠可显著减轻大鼠的肠道上皮细胞旁通透性和内脏痛觉过敏的变化，在大鼠的亚群中。鲁比前列酮还可预防 WAS 诱导的上皮紧密连接蛋白闭合蛋白（Ocln）减少。为了解决内脏疼痛的程度是否与改变的肠道通透性的程度相关的问题，我们因为疼痛反应的个体差异很大，所以在同一动物中测量了这两个终点。我们的研究表明，内脏疼痛和结肠通透性的增加呈正相关（0.6008，P = 0.0084）。最后，在对照动物的远端结肠中体内暴露于 Ocln siRNA 显示，Ocln 蛋白的敲低与增加的细胞旁通透性和增强的内脏疼痛呈负相关，类似于在 WAS 反应性大鼠中观察到的水平。这些数据支持 Ocln 在应激诱导的结肠通透性增加的发展中可能发挥重要作用。我们相信这是首次证明慢性应激相关内脏痛觉过敏的程度与改变的结肠上皮细胞旁通透性的程度直接相关。
