Optogenetic inhibition of the colon epithelium reduces hypersensitivity in a mouse model of inflammatory bowel disease.
Optogenetic inhibition of the colon epithelium reduces hypersensitivity in a mouse model of inflammatory bowel disease.
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DOI：
10.1097/j.pain.0000000000002110
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发表时间：
2021-04-01
期刊：
影响因子：
7.4
通讯作者：
Albers KM
中科院分区：
文献类型：
--
作者：
Najjar SA;Ejoh LL;Loeza-Alcocer E;Edwards BS;Smith-Edwards KM;Epouhe AY;Gold MS;Davis BM;Albers KM
内脏疼痛是炎症性肠病的常见症状，难以治疗。疼痛和超敏反应由支配结肠的外源性初级传入神经元（ExPANs）介导。最近的研究表明，结肠上皮有助于启动ExPAN放电和伤害性反应。基于这些发现，我们假设上皮有助于炎症诱导的超敏反应。这一假说的一个关键预测是，抑制上皮细胞将减弱伤害性信号传导和炎症超敏反应。为了验证这一假设，将抑制性黄光激活蛋白质古紫质靶向肠上皮（villin-Arch）或神经支配结肠的ExpPANs（TRPV 1-Arch）。内脏敏感性通过测量内脏对结肠直肠扩张（CRD）的反应（VMR）进行评估，有和没有结肠腔的黄光照明。在健康的villin-Arch小鼠中抑制结肠上皮显著减少了CRD诱导的VMR。使用TRPV 1-Arch小鼠在CRD期间直接抑制ExPAN显示ExPAN和上皮抑制在减少VMR至CRD方面类似地有效。然后，我们研究了上皮和ExPAN抑制在葡聚糖硫酸钠炎症性肠病模型中的作用。抑制结肠上皮细胞显著降低葡聚糖硫酸钠诱导的超敏反应，与抑制ExpPANs相当。总之，这些结果揭示了靶向结肠上皮用于治疗疼痛的潜力。
Visceral pain is a prevalent symptom of inflammatory bowel disease that can be difficult to treat. Pain and hypersensitivity are mediated by extrinsic primary afferent neurons (ExPANs) that innervate the colon. Recent studies indicate that the colon epithelium contributes to initiating ExPAN firing and nociceptive responses. Based on these findings, we hypothesized that the epithelium contributes to inflammation-induced hypersensitivity. A key prediction of this hypothesis is that inhibition of the epithelium would attenuate nociceptive signaling and inflammatory hypersensitivity. To test this hypothesis, the inhibitory yellow light–activated protein archaerhodopsin was targeted to the intestinal epithelium (villin-Arch) or the ExPANs (TRPV1-Arch) that innervate the colon. Visceral sensitivity was assessed by measuring the visceromotor response (VMR) to colorectal distension (CRD), with and without yellow light illumination of the colon lumen. Inhibition of the colon epithelium in healthy villin-Arch mice significantly diminished the CRD-induced VMR. Direct inhibition of ExPANs during CRD using TRPV1-Arch mice showed that ExPAN and epithelial inhibition were similarly effective in reducing the VMR to CRD. We then investigated the effect of epithelial and ExPAN inhibition in the dextran sulfate sodium model of inflammatory bowel disease. Inhibition of the colon epithelium significantly decreased dextran sulfate sodium–induced hypersensitivity and was comparable with the inhibition of ExPANs. Together, these results reveal the potential of targeting the colon epithelium for the treatment of pain.
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影响因子：
5.6
作者：
Farrell KE;Callister RJ;Keely S
通讯作者：
Keely S
影响因子：
2
作者：
Gupta, Gopal N.;Lu, Shao-Gang;Chail, Toby C.
通讯作者：
Chail, Toby C.
影响因子：
5.3
作者：
Makadia, Payal A.;Najjar, Sarah A.;Davis, Brian M.
通讯作者：
Davis, Brian M.
DOI：
10.1073/pnas.1804938115
发表时间：
2018-08-07
影响因子：
11.1
作者：
Alcaino C;Knutson KR;Treichel AJ;Yildiz G;Strege PR;Linden DR;Li JH;Leiter AB;Szurszewski JH;Farrugia G;Beyder A
通讯作者：
Beyder A
影响因子：
64.5
作者：
Bellono NW;Bayrer JR;Leitch DB;Castro J;Zhang C;O'Donnell TA;Brierley SM;Ingraham HA;Julius D
通讯作者：
Julius D