Morphine pharmacokinetics and opioid transporter expression at the blood-retina barrier of male and female mice.
Morphine pharmacokinetics and opioid transporter expression at the blood-retina barrier of male and female mice.
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DOI：
10.3389/fphar.2023.1206104
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发表时间：
2023
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
阿片类药物是治疗中度到重度疼痛的有效止痛剂，然而，必须权衡它们的使用和危险的副作用。对阿片类药物药代动力学的研究提供了有关靶上和靶外药物效应的重要信息。我们最近的工作表明，长期全身暴露时，吗啡在小鼠视网膜中的沉积和积累浓度高于大脑。我们还发现P-糖蛋白(P-gp)在视网膜的表达减少，P-gp是血脑屏障(BBB)的主要阿片挤出物质。在这里，我们系统地询问了三种可能的阿片转运体在血-视网膜屏障(BRB)的表达：P-gp、乳腺癌耐药蛋白(BCRP)和多药耐药蛋白2(MRP2)。利用免疫组织化学方法，我们发现P-gp和BCRP在小鼠视网膜的内侧BRB有很强的表达，但不表达MRP2。以前的研究表明，P-gp的表达可能受性激素的调节。然而，在急性吗啡治疗中，我们发现雌孕激素比例高或低的男性和女性在视网膜或大脑中的吗啡沉积水平没有性别差异，也没有发现转运蛋白在视网膜中的表达存在性别差异。重要的是，我们发现P-gp而不是BCRP的表达与视网膜中吗啡浓度显著相关，这表明P-gp是BRB的主要阿片转运体。此外，荧光外渗研究表明，慢性吗啡治疗并不改变血脑屏障或血脑屏障的通透性。综上所述，这些数据表明，P-gp表达的减少介导了全身给药时视网膜吗啡的积聚，进而对昼夜节律的光夹带产生了潜在的影响。
Opioids are effective analgesics for treating moderate to severe pain, however, their use must be weighed against their dangerous side effects. Investigations into opioid pharmacokinetics provide crucial information regarding both on- and off-target drug effects. Our recent work showed that morphine deposits and accumulates in the mouse retina at higher concentrations than in the brain upon chronic systemic exposure. We also found reduced retinal expression of P-glycoprotein (P-gp), a major opioid extruder at the blood-brain barrier (BBB). Here, we systematically interrogated the expression of three putative opioid transporters at the blood-retina barrier (BRB): P-gp, breast cancer resistance protein (Bcrp) and multidrug resistance protein 2 (Mrp2). Using immunohistochemistry, we found robust expression of P-gp and Bcrp, but not Mrp2, at the inner BRB of the mouse retina. Previous studies have suggested that P-gp expression may be regulated by sex hormones. However, upon acute morphine treatment we found no sex differences in morphine deposition levels in the retina or brain, nor on transporter expression in the retinas of males and females with a high or low estrogen:progesterone ratio. Importantly, we found that P-gp, but not Bcrp, expression significantly correlated with morphine concentration in the retina, suggesting P-gp is the predominant opioid transporter at the BRB. In addition, fluorescence extravasation studies revealed that chronic morphine treatment did not alter the permeability of either the BBB or BRB. Together, these data suggest that reduced P-gp expression mediates retinal morphine accumulation upon systemic delivery, and in turn, potential effects on circadian photoentrainment.
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影响因子：
5.6
作者：
Cleymaet AM;Berezin CT;Vigh J
通讯作者：
Vigh J
影响因子：
2.2
作者：
Bévalot F;Cartiser N;Bottinelli C;Fanton L;Guitton J
通讯作者：
Guitton J
影响因子：
4.3
作者：
Bergum, Nikolas;Berezin, Casey-Tyler;Vigh, Jozsef
通讯作者：
Vigh, Jozsef
DOI：
10.3390/ph15050527
发表时间：
2022-04-25
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.4
作者：
Costes, SV;Daelemans, D;Lockett, S
通讯作者：
Lockett, S