Loading…

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

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...

Full description

Saved in:
Bibliographic Details
Published in:Frontiers in pharmacology 2023-06, Vol.14, p.1206104-1206104
Main Authors: Berezin, Casey-Tyler, Bergum, Nikolas, Torres Lopez, Glenda M, Vigh, Jozsef
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c469t-3ec4d5e0ac140939c44302fdf40f4ab7ab7387da25dbfa4c3923e2b1dda5e4753
cites cdi_FETCH-LOGICAL-c469t-3ec4d5e0ac140939c44302fdf40f4ab7ab7387da25dbfa4c3923e2b1dda5e4753
container_end_page 1206104
container_issue
container_start_page 1206104
container_title Frontiers in pharmacology
container_volume 14
creator Berezin, Casey-Tyler
Bergum, Nikolas
Torres Lopez, Glenda M
Vigh, Jozsef
description 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.
doi_str_mv 10.3389/fphar.2023.1206104
format article
fullrecord <record><control><sourceid>proquest_doaj_</sourceid><recordid>TN_cdi_doaj_primary_oai_doaj_org_article_8bc47fe565fb4332a6f1c8e6fc0a2ad5</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><doaj_id>oai_doaj_org_article_8bc47fe565fb4332a6f1c8e6fc0a2ad5</doaj_id><sourcerecordid>2832570898</sourcerecordid><originalsourceid>FETCH-LOGICAL-c469t-3ec4d5e0ac140939c44302fdf40f4ab7ab7387da25dbfa4c3923e2b1dda5e4753</originalsourceid><addsrcrecordid>eNpVkc1u3CAUha2qVRKleYEsKpbdeAJcbONVVUVNGylVN-0aXcMlQ2obFzxV-_axZyZRgpC4wDkfP6coLgXfAOj2yk9bTBvJJWyE5LXg6k1xJuoaylYL-fZFfVpc5PzAlwZtC7U6KU6hAa2VEmdF_B7TtA0jsZU3oI2_l8kcbGY4OhanEINjc8IxTzHNlBj9mxLlHOLIcGbzlljXx-jKtLhGZB2mFBZZ9GzAnvYUT_tyCJbeF-889pkujuN58evmy8_rb-Xdj6-315_vSqvqdi6BrHIVcbRC8RZaqxRw6Z1X3CvsmqWDbhzKynUelYVWAslOOIcVqaaC8-L2wHURH8yUwoDpv4kYzH4hpnuDaXlmT0Z3VjWeqrrynQKQWHthNdXecpToVtanA2vadQM5S-PyH_0r6OudMWzNffxrBAcumkovhI9HQop_dpRnM4Rsqe9xpLjLRmqQVcN1u0rlQWpTzDmRfz5HcLMmb_bJmzV5c0x-MX14ecNny1PO8Ajzkq5O</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2832570898</pqid></control><display><type>article</type><title>Morphine pharmacokinetics and opioid transporter expression at the blood-retina barrier of male and female mice</title><source>PubMed Central</source><creator>Berezin, Casey-Tyler ; Bergum, Nikolas ; Torres Lopez, Glenda M ; Vigh, Jozsef</creator><creatorcontrib>Berezin, Casey-Tyler ; Bergum, Nikolas ; Torres Lopez, Glenda M ; Vigh, Jozsef</creatorcontrib><description>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.</description><identifier>ISSN: 1663-9812</identifier><identifier>EISSN: 1663-9812</identifier><identifier>DOI: 10.3389/fphar.2023.1206104</identifier><identifier>PMID: 37388441</identifier><language>eng</language><publisher>Switzerland: Frontiers Media S.A</publisher><subject>ABC transporters ; blood-brain barrier ; blood-retina barrier ; morphine ; P-glycoprotein ; Pharmacology ; sex differences</subject><ispartof>Frontiers in pharmacology, 2023-06, Vol.14, p.1206104-1206104</ispartof><rights>Copyright © 2023 Berezin, Bergum, Torres Lopez and Vigh.</rights><rights>Copyright © 2023 Berezin, Bergum, Torres Lopez and Vigh. 2023 Berezin, Bergum, Torres Lopez and Vigh</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c469t-3ec4d5e0ac140939c44302fdf40f4ab7ab7387da25dbfa4c3923e2b1dda5e4753</citedby><cites>FETCH-LOGICAL-c469t-3ec4d5e0ac140939c44302fdf40f4ab7ab7387da25dbfa4c3923e2b1dda5e4753</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10301758/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10301758/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37388441$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Berezin, Casey-Tyler</creatorcontrib><creatorcontrib>Bergum, Nikolas</creatorcontrib><creatorcontrib>Torres Lopez, Glenda M</creatorcontrib><creatorcontrib>Vigh, Jozsef</creatorcontrib><title>Morphine pharmacokinetics and opioid transporter expression at the blood-retina barrier of male and female mice</title><title>Frontiers in pharmacology</title><addtitle>Front Pharmacol</addtitle><description>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.</description><subject>ABC transporters</subject><subject>blood-brain barrier</subject><subject>blood-retina barrier</subject><subject>morphine</subject><subject>P-glycoprotein</subject><subject>Pharmacology</subject><subject>sex differences</subject><issn>1663-9812</issn><issn>1663-9812</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>DOA</sourceid><recordid>eNpVkc1u3CAUha2qVRKleYEsKpbdeAJcbONVVUVNGylVN-0aXcMlQ2obFzxV-_axZyZRgpC4wDkfP6coLgXfAOj2yk9bTBvJJWyE5LXg6k1xJuoaylYL-fZFfVpc5PzAlwZtC7U6KU6hAa2VEmdF_B7TtA0jsZU3oI2_l8kcbGY4OhanEINjc8IxTzHNlBj9mxLlHOLIcGbzlljXx-jKtLhGZB2mFBZZ9GzAnvYUT_tyCJbeF-889pkujuN58evmy8_rb-Xdj6-315_vSqvqdi6BrHIVcbRC8RZaqxRw6Z1X3CvsmqWDbhzKynUelYVWAslOOIcVqaaC8-L2wHURH8yUwoDpv4kYzH4hpnuDaXlmT0Z3VjWeqrrynQKQWHthNdXecpToVtanA2vadQM5S-PyH_0r6OudMWzNffxrBAcumkovhI9HQop_dpRnM4Rsqe9xpLjLRmqQVcN1u0rlQWpTzDmRfz5HcLMmb_bJmzV5c0x-MX14ecNny1PO8Ajzkq5O</recordid><startdate>20230614</startdate><enddate>20230614</enddate><creator>Berezin, Casey-Tyler</creator><creator>Bergum, Nikolas</creator><creator>Torres Lopez, Glenda M</creator><creator>Vigh, Jozsef</creator><general>Frontiers Media S.A</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20230614</creationdate><title>Morphine pharmacokinetics and opioid transporter expression at the blood-retina barrier of male and female mice</title><author>Berezin, Casey-Tyler ; Bergum, Nikolas ; Torres Lopez, Glenda M ; Vigh, Jozsef</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c469t-3ec4d5e0ac140939c44302fdf40f4ab7ab7387da25dbfa4c3923e2b1dda5e4753</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>ABC transporters</topic><topic>blood-brain barrier</topic><topic>blood-retina barrier</topic><topic>morphine</topic><topic>P-glycoprotein</topic><topic>Pharmacology</topic><topic>sex differences</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Berezin, Casey-Tyler</creatorcontrib><creatorcontrib>Bergum, Nikolas</creatorcontrib><creatorcontrib>Torres Lopez, Glenda M</creatorcontrib><creatorcontrib>Vigh, Jozsef</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>Frontiers in pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Berezin, Casey-Tyler</au><au>Bergum, Nikolas</au><au>Torres Lopez, Glenda M</au><au>Vigh, Jozsef</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Morphine pharmacokinetics and opioid transporter expression at the blood-retina barrier of male and female mice</atitle><jtitle>Frontiers in pharmacology</jtitle><addtitle>Front Pharmacol</addtitle><date>2023-06-14</date><risdate>2023</risdate><volume>14</volume><spage>1206104</spage><epage>1206104</epage><pages>1206104-1206104</pages><issn>1663-9812</issn><eissn>1663-9812</eissn><abstract>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.</abstract><cop>Switzerland</cop><pub>Frontiers Media S.A</pub><pmid>37388441</pmid><doi>10.3389/fphar.2023.1206104</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1663-9812
ispartof Frontiers in pharmacology, 2023-06, Vol.14, p.1206104-1206104
issn 1663-9812
1663-9812
language eng
recordid cdi_doaj_primary_oai_doaj_org_article_8bc47fe565fb4332a6f1c8e6fc0a2ad5
source PubMed Central
subjects ABC transporters
blood-brain barrier
blood-retina barrier
morphine
P-glycoprotein
Pharmacology
sex differences
title Morphine pharmacokinetics and opioid transporter expression at the blood-retina barrier of male and female mice
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T02%3A30%3A59IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_doaj_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Morphine%20pharmacokinetics%20and%20opioid%20transporter%20expression%20at%20the%20blood-retina%20barrier%20of%20male%20and%20female%20mice&rft.jtitle=Frontiers%20in%20pharmacology&rft.au=Berezin,%20Casey-Tyler&rft.date=2023-06-14&rft.volume=14&rft.spage=1206104&rft.epage=1206104&rft.pages=1206104-1206104&rft.issn=1663-9812&rft.eissn=1663-9812&rft_id=info:doi/10.3389/fphar.2023.1206104&rft_dat=%3Cproquest_doaj_%3E2832570898%3C/proquest_doaj_%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c469t-3ec4d5e0ac140939c44302fdf40f4ab7ab7387da25dbfa4c3923e2b1dda5e4753%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2832570898&rft_id=info:pmid/37388441&rfr_iscdi=true