Morphine pharmacokinetics and opioid transporter expression at the blood-retina barrier of male and female mice

Frontiers in Pharmacology

Pharmacology

Casey-Tyler Berezin¹  Jozsef Vigh²  Nikolas Bergum³  Glenda M. Torres Lopez³ 

[1] Cell and Molecular Biology Graduate Program, Colorado State University, Fort Collins, CO, United States;Cell and Molecular Biology Graduate Program, Colorado State University, Fort Collins, CO, United States;Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, United States;Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, United States;

关键词: blood-retina barrier;    morphine;    P-glycoprotein;    ABC transporters;    sex differences;    blood-brain barrier;   

DOI  :  10.3389/fphar.2023.1206104

 received in 2023-04-14, accepted in 2023-06-01,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

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Copyright © 2023 Berezin, Bergum, Torres Lopez and Vigh.