Abstract
Poor antiretroviral penetration may contribute to human immunodeficiency virus (HIV) persistence within the brain and to neurocognitive deficits in opiate abusers. To investigate this problem, HIV-1 Tat protein and morphine effects on blood–brain barrier (BBB) permeability and drug brain penetration were explored using a conditional HIV-1 Tat transgenic mouse model. Tat and morphine effects on the leakage of fluorescently labeled dextrans (10-, 40-, and 70-kDa) into the brain were assessed. To evaluate effects on antiretroviral brain penetration, Tat+ and Tat− mice received three antiretroviral drugs (dolutegravir, abacavir, and lamivudine) with or without concurrent morphine exposure. Antiretroviral and morphine brain and plasma concentrations were determined by LC-MS/MS. Morphine exposure, and, to a lesser extent, Tat, significantly increased tracer leakage from the vasculature into the brain. Despite enhanced BBB breakdown evidenced by increased tracer leakiness, morphine exposure led to significantly lower abacavir concentrations within the striatum and significantly less dolutegravir within the hippocampus and striatum (normalized to plasma). P-glycoprotein, an efflux transporter for which these drugs are substrates, expression and function were significantly increased in the brains of morphine-exposed mice compared to mice not exposed to morphine. These findings were consistent with lower antiretroviral concentrations in brain tissues examined. Lamivudine concentrations were unaffected by Tat or morphine exposure. Collectively, our investigations indicate that Tat and morphine differentially alter BBB integrity. Morphine decreased brain concentrations of specific antiretroviral drugs, perhaps via increased expression of the drug efflux transporter, P-glycoprotein.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abbott NJ, Rönnbäck L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7:41–53
Abbott NJ, Patabendige AAK, Dolman DEM et al (2010) Structure and function of the blood-brain barrier. Neurobiol Dis 37:13–25
Achanti S, Katta RR (2017) Corrigendum to “high-throughput liquid chromatography tandem mass spectrometry method for simultaneous determination of fampridine, paroxetine, and quinidine in rat plasma: application to in vivo perfusion study” [J Food Drug Anal 24 (2016) 866-875]. J Food Drug Anal 25:1008. https://doi.org/10.1016/j.jfda.2017.01.006
Alhaddad H, Cisternino S, Declèves X et al (2012) Respiratory toxicity of buprenorphine results from the blockage of P-glycoprotein-mediated efflux of norbuprenorphine at the blood–brain barrier in mice. Crit Care Med 40:3215–3223. https://doi.org/10.1097/CCM.0b013e318265680a
Andras IE, Pu H, Deli MA et al (2003) HIV-1 Tat protein alters tight junction protein expression and distribution in cultured brain endothelial cells. J Neurosci Res 74:255–265
András IE, Pu H, Tian J et al (2005) Signaling mechanisms of HIV-1 tat-induced alterations of claudin-5 expression in brain endothelial cells. J Cereb Blood Flow Metab 25:1159–1170
Aquilante CL, Letrent SP, Pollack GM, Brouwer KL (2000) Increased brain P-glycoprotein in morphine tolerant rats. Life Sci 66:PL47–PL51
Banerjee A, Zhang X, Manda KR et al (2010) HIV proteins (gp120 and tat) and methamphetamine in oxidative stress-induced damage in the brain: potential role of the thiol antioxidant N-acetylcysteine amide. Free Radic Biol Med 48:1388–1398
Bauer B, Hartz AMS, Fricker G, Miller DS (2004) Pregnane X receptor up-regulation of P-glycoprotein expression and transport function at the blood-brain barrier. Mol Pharmacol 66:413–419
Ben-Zvi A, Lacoste B, Kur E et al (2014) Mfsd2a is critical for the formation and function of the blood-brain barrier. Nature 509:507–511
Binkhathlan Z, Hamdy DA, Brocks DR, Lavasanifar A (2010) Pharmacokinetics of PSC 833 (valspodar) in its Cremophor EL formulation in rat. Xenobiotica 40:55–61. https://doi.org/10.3109/00498250903331056
Bogulavsky JJ, Gregus AM, Kim PT-H et al (2009) Deletion of the glutamate receptor 5 subunit of kainate receptors affects the development of morphine tolerance. J Pharmacol Exp Ther 328:579–587. https://doi.org/10.1124/jpet.108.144121
Boven LA, Middel J, Verhoef J et al (2000) Monocyte infiltration is highly associated with loss of the tight junction protein zonula occludens in HIV-1-associated dementia. Neuropathol Appl Neurobiol 26:356–360. https://doi.org/10.1046/j.1365-2990.2000.00255.x
Bruce-Keller AJ, Turchan-Cholewo J, Smart EJ et al (2008) Morphine causes rapid increases in glial activation and neuronal injury in the striatum of inducible HIV-1 tat transgenic mice. Glia 56:1414–1427. https://doi.org/10.1002/glia.20708
Buckner CM, Luers AJ, Calderon TM et al (2006) Neuroimmunity and the blood-brain barrier: molecular regulation of leukocyte transmigration and viral entry into the nervous system with a focus on neuroAIDS. J NeuroImmune Pharmacol 1:160–181. https://doi.org/10.1007/s11481-006-9017-3
Buckner CM, Calderon TM, Williams DW et al (2011) Characterization of monocyte maturation/differentiation that facilitates their transmigration across the blood-brain barrier and infection by HIV: implications for NeuroAIDS. Cell Immunol 267:109–123
Casado JL, Marín A, Moreno A et al (2014) Central nervous system antiretroviral penetration and cognitive functioning in largely pretreated HIV-infected patients. J Neuro-Oncol 20:54–61. https://doi.org/10.1007/s13365-013-0228-0
Chaudhuri A, Duan F, Morsey B et al (2008a) HIV-1 activates proinflammatory and interferon-inducible genes in human brain microvascular endothelial cells: putative mechanisms of blood-brain barrier dysfunction. J Cereb Blood Flow Metab 28:697–711. https://doi.org/10.1038/sj.jcbfm.9600567
Chaudhuri A, Yang B, Gendelman HE et al (2008b) STAT1 signaling modulates HIV-1 – induced inflammatory responses and leukocyte transmigration across the blood-brain barrier. Blood 111:2062–2072. https://doi.org/10.1182/blood-2007-05-091207
Chefer VI, Shippenberg TS (2009) Augmentation of morphine-induced sensitization but reduction in morphine tolerance and reward in delta-opioid receptor knockout mice. Neuropsychopharmacology 34:887–898. https://doi.org/10.1038/npp.2008.128
Coley JS, Calderon TM, Gaskill PJ et al (2015) Dopamine increases CD14+CD16+ monocyte migration and adhesion in the context of substance abuse and HIV neuropathogenesis. PLoS One 10:e0117450
Cysique LA, Brew BJ (2009) Neuropsychological functioning and antiretroviral treatment in HIV/AIDS: a review. Neuropsychol Rev 19:169–185. https://doi.org/10.1007/s11065-009-9092-3
Dallasta LM, Pisarov LA, Esplen JE et al (1999) Blood-brain barrier tight junction disruption in human immunodeficiency virus-1 encephalitis. Am J Pathol 155:1915–1927
Dauchy S, Miller F, Couraud PO et al (2009) Expression and transcriptional regulation of ABC transporters and cytochromes P450 in hCMEC/D3 human cerebral microvascular endothelial cells. Biochem Pharmacol 77:897–909. https://doi.org/10.1016/j.bcp.2008.11.001
Dehouck MP, Méresse S, Delorme P et al (1990) An easier, reproducible, and mass-production method to study the blood-brain barrier in vitro. J Neurochem 54:1798–1801
Dohgu S, Takata F, Yamauchi A et al (2005) Brain pericytes contribute to the induction and up-regulation of blood-brain barrier functions through transforming growth factor-beta production. Brain Res 1038:208–215
Donahoe RM, Vlahov D (1998) Opiates as potential cofactors in progression of HIV-1 infections to AIDS. J Neuroimmunol 83:77–87. https://doi.org/10.1016/S0165-5728(97)00224-5
Dutta R, Roy S (2012) Mechanism(s) involved in opioid drug abuse modulation of HAND. Curr HIV Res 10:469–477. https://doi.org/10.2174/157016212802138805
Edwards JE, Brouwer KR, McNamara PJ (2002) GF120918, a P-glycoprotein modulator, increases the concentration of unbound amprenavir in the central nervous system in rats. Antimicrob Agents Chemother 46:2284–2286. https://doi.org/10.1128/AAC.46.7.2284
El-Hage N, Gurwell JA, Singh IN et al (2005) Synergistic increases in intracellular Ca2+, and the release of MCP-1, RANTES, and IL-6 by astrocytes treated with opiates and HIV-1 Tat. Glia 50:91–106
El-Hage N, Wu G, Wang J et al (2006) HIV-1 Tat and opiate-induced changes in astrocytes promote chemotaxis of microglia through the expression of MCP-1 and alternative chemokines. Glia 53:132–146. https://doi.org/10.1002/glia.20262
El-Hage N, Bruce-Keller AJ, Yakovleva T et al (2008) Morphine exacerbates HIV-1 Tat-induced cytokine production in astrocytes through convergent effects on [Ca2+]i, NF-κB trafficking and transcription. PLoS One 3:e4093. https://doi.org/10.1371/journal.pone.0004093.t001
Ellis R, Langford D, Masliah E (2007) HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci 8:33–44
Eugenin EA (2006) CCL2/monocyte chemoattractant protein-1 mediates enhanced transmigration of human immunodeficiency virus (HIV)-infected leukocytes across the blood-brain barrier: a potential mechanism of HIV-CNS invasion and NeuroAIDS. J Neurosci 26:1098–1106
Eugenin EA, Clements JE, Zink MC, Berman JW (2011) Human immunodeficiency virus infection of human astrocytes disrupts blood-brain barrier integrity by a gap junction-dependent mechanism. J Neurosci 31:9456–9465
Fitting S, Xu R, Bull C et al (2010a) Interactive comorbidity between opioid drug abuse and HIV-1 Tat: chronic exposure augments spine loss and sublethal dendritic pathology in striatal neurons. Am J Pathol 177:1397–1410. https://doi.org/10.2353/ajpath.2010.090945
Fitting S, Zou S, Chen W et al (2010b) Regional heterogeneity and diversity in cytokine and chemokine production by astroglia: differential responses to HIV-1 Tat, gp120, and morphine revealed by multiplex analysis. J Proteome Res 9:1795–1804. https://doi.org/10.1021/pr900926n
Fitting S, Ignatowska-Jankowska BM, Bull C et al (2013) Synaptic dysfunction in the hippocampus accompanies learning and memory deficits in HIV-1 Tat transgenic mice. Biol Psychiatry 73:443–453. https://doi.org/10.1016/j.biopsych.2012.09.026.Synaptic
Fitting S, Knapp PE, Zou S et al (2014) Interactive HIV-1 Tat and morphine-induced synaptodendritic injury is triggered through focal disruptions in Na+ influx, mitochondrial instability, and Ca2+ overload. J Neurosci 34:12850–12864
Fujimura RK, Goodkin K, Petito CK et al (1997) HIV-1 proviral DNA load across neuroanatomic regions of individuals with evidence for HIV-1-associated dementia. J Acquir Immune Defic Syndr Hum Retrovirol 16:146–152. https://doi.org/10.1097/00042560-199711010-00002
Gan L-S, Hsyu P-H, Pritchard JF, Thakker DR (1993) Mechanism of intestinal absorption of ranitidine and ondeansetron: transport across Caco-2 cell monolayers. Pharm Res 10:1722–1725
Gandhi N, Saiyed ZM, Napuri J et al (2010) Interactive role of human immunodeficiency virus type 1 (HIV-1) clade-specific tat protein and cocaine in blood-brain barrier dysfunction: implications for HIV-1-associated neurocognitive disorder. J Neuro-Oncol 16:294–305
Ghazi-Khansari M, Zendehdel R, Pirali-Hamedani M, Amini M (2006) Determination of morphine in the plasma of addicts in using zeolite Y extraction following high-performance liquid chromatography. Clin Chim Acta 364:235–238. https://doi.org/10.1016/j.cccn.2005.07.002
Giri N, Shaik N, Pan G et al (2008) Investigation of the role of breast cancer resistance protein (Bcrp/Abcg2) on pharmacokinetics and central nervous system penetration of abacavir and zidovudine in the mouse. Drug Metab Dispos 36:1476–1484. https://doi.org/10.1124/dmd.108.020974.roviral
Gurwell JA, Nath A, Sun Q et al (2001) Synergistic neurotoxicity of opioids and human immunodeficiency virus-1 Tat protein in striatal neurons in vitro. Neuroscience 102:555–563
Hanamsagar R, Alter MD, Block CS et al (2017) Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity. Glia 65:1504–1520. https://doi.org/10.1002/glia.23176
Hauser KF, El-Hage N, Stiene-Martin A et al (2007) HIV-1 neuropathogenesis: glial mechanisms revealed through substance abuse. J Neurochem 100:567–586
Hauser KF, Hahn YK, Adjan VV et al (2009) HIV-1 Tat and morphine have interactive effects on oligodendrocyte survival and morphology. Glia 57:194–206. https://doi.org/10.1002/glia.20746
Hawkins BT, Egleton RD (2006) Fluorescence imaging of blood-brain barrier disruption. J Neurosci Methods 151:262–267. https://doi.org/10.1016/j.jneumeth.2005.08.006
Hayashi Y, Nomura M, Yamagishi S et al (1997) Induction of various blood-brain barrier properties in non-neural endothelial cells by close apposition to co-cultured astrocytes. Glia 19:13–26
Hayashi K, Pu H, Tian J et al (2005) HIV-Tat protein induces P-glycoprotein expression in brain microvascular endothelial cells. J Neurochem 93:1231–1241. https://doi.org/10.1111/j.1471-4159.2005.03114.x
Hayashi K, Pu H, Andras IE et al (2006) HIV-TAT protein upregulates expression of multidrug resistance protein 1 in the blood-brain barrier. J Cereb Blood Flow Metab 26:1052–1065. https://doi.org/10.1038/sj.jcbfm.9600254
Hubensack M, Muller C, Hocherl P et al (2008) Effect of the ABCB1 modulators elacridar and tariquidar on the distribution of paclitaxel in nude mice. J Cancer Res Clin Oncol 134:597–607. https://doi.org/10.1007/s00432-007-0323-9
Janzer RC, Raff MC (1987) Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 325:253–257. https://doi.org/10.1038/325253a0
Kanmogne GD, Kennedy RC, Grammas P (2002) HIV-1 gp120 proteins and gp160 peptides are toxic to brain endothelial cells and neurons: possible pathway for HIV entry into the brain and HIV-associated dementia. J Neuropathol Exp Neurol 61:992–1000
Kanmogne GD, Schall K, Leibhart J et al (2007) HIV-1 gp120 compromises blood-brain barrier integrity and enhances monocyte migration across blood-brain barrier: implication for viral neuropathogenesis. J Cereb Blood Flow Metab 27:123–134
Kis O, Robillard K, Chan GNY, Bendayan R (2010) The complexities of antiretroviral drug-drug interactions: role of ABC and SLC transporters. Trends Pharmacol Sci 31:22–35. https://doi.org/10.1016/j.tips.2009.10.001
Kumar R, Orsoni S, Norman L et al (2006) Chronic morphine exposure causes pronounced virus replication in cerebral compartment and accelerated onset of AIDS in SIV/SHIV-infected Indian rhesus macaques. Virology 354:192–206. https://doi.org/10.1016/j.virol.2006.06.020
Kusuhara H, Suzuki H, Terasaki T et al (1997) P-Glycoprotein mediates the efflux of quinidine across the blood-brain barrier. J Pharmacol Exp Ther 283:574–580
Leibrand CR, Paris JJ, Ghandour MS et al (2017) HIV-1 Tat disrupts blood-brain barrier integrity and increases phagocytic perivascular macrophages and microglia in the dorsal striatum of transgenic mice. Neurosci Lett 640:136–143. https://doi.org/10.1016/j.neulet.2016.12.073
Li Y, Wang X, Tian S et al (2002) Methadone enhances human immunodeficiency virus infection of human immune cells. J Infect Dis 185:118–122. https://doi.org/10.1016/j.biotechadv.2011.08.021.Secreted
Liebner S, Dijkhuizen RM, Reiss Y et al (2018) Functional morphology of the blood–brain barrier in health and disease. Acta Neuropathol 311–336. https://doi.org/10.1007/s00401-018-1815-1
Louboutin J-P, Strayer DS (2012) Blood-brain barrier abnormalities caused by HIV-1 gp120: mechanistic and therapeutic implications. Sci World J 2012:1–15. https://doi.org/10.1100/2012/482575
Louboutin J-P, Agrawal L, Reyes B a S et al (2010) HIV-1 gp120-induced injury to the blood-brain barrier: role of metalloproteinases 2 and 9 and relationship to oxidative stress. J Neuropathol Exp Neurol 69:801–816. https://doi.org/10.1097/NEN.0b013e3181e8c96f
Mahajan SD, Aalinkeel R, Sykes DE et al (2008) Tight junction regulation by morphine and HIV-1 Tat modulates blood-brain barrier permeability. J Clin Immunol 28:528–541. https://doi.org/10.1007/s10875-008-9208-1
Marks WD, Paris JJ, Schier CJ et al (2016) HIV-1 Tat causes cognitive deficits and selective loss of parvalbumin, somatostatin, and neuronal nitric oxide synthase expressing hippocampal CA1 interneuron subpopulations. J Neuro-Oncol 1–16. https://doi.org/10.1007/s13365-016-0447-2
McLane VD, Kumar S, Leeming R et al (2018) Morphine-potentiated cognitive deficits correlate to suppressed hippocampal iNOS RNA expression and an absent type 1 interferon response in LP-BM5 murine AIDS. J Neuroimmunol 319:117–129. https://doi.org/10.1016/j.jneuroim.2018.02.017
Meng J, Yu H, Ma J et al (2013) Morphine induces bacterial translocation in mice by compromising intestinal barrier function in a TLR-dependent manner. PLoS One 8:e54040
Miller DS (2010) Regulation of P-glycoprotein and other ABC drug transporters at the blood-brain barrier. Trends Pharmacol Sci 31:246–254
Miller DS, Bauer B, Hartz AMS (2008) Modulation of P-glycoprotein at the blood-brain barrier: opportunities to improve central nervous system pharmacotherapy. Pharmacol Rev 60:196–209
Minuesa G, Volk C, Molina-Arcas M et al (2009) Transport of lamivudine [(-)-beta-L-2′,3′-dideoxy-3′-thiacytidine] and high-affinity interaction of nucleoside reverse transcriptase inhibitors with human organic cation transporters 1, 2, and 3. J Pharmacol Exp Ther 329:252–261. https://doi.org/10.1124/jpet.108.146225
Miyata KI, Nakagawa Y, Kimura Y et al (2016) In vitro and in vivo evaluations of the P-glycoprotein-mediated efflux of dibenzoylhydrazines. Toxicol Appl Pharmacol 298:40–47. https://doi.org/10.1016/j.taap.2016.03.008
Nair AB, Jacob S (2016) A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 7:27–31. https://doi.org/10.4103/0976-0105.177703
Nakamuta S, Endo H, Higashi Y et al (2008) Human immunodeficiency virus type 1 gp120-mediated disruption of tight junction proteins by induction of proteasome-mediated degradation of zonula occludens-1 and -2 in human brain microvascular endothelial cells. J Neuro-Oncol 14:186–195. https://doi.org/10.1080/13550280801993630
Nath A (2015) Eradication of human immunodeficiency virus from brain reservoirs. J Neuro-Oncol 21:227–234. https://doi.org/10.1007/s13365-014-0291-1
Nath A, Hauser KF, Wojna V et al (2002) Molecular basis for interactions of HIV and drugs of abuse. J Acquir Immune Defic Syndr 31(Suppl 2):S62–S69. https://doi.org/10.1097/00126334-200210012-00006
Ngwainmbi J, De DD, Smith TH et al (2014) Effects of HIV-1 Tat on enteric neuropathogenesis. J Neurosci 34:14243–14251. https://doi.org/10.1523/JNEUROSCI.2283-14.2014
Persidsky Y, Ghorpade A, Rasmussen J et al (1999) Microglial and astrocyte chemokines regulate monocyte migration through the blood-brain barrier in human immunodeficiency virus-1 encephalitis. Am J Pathol 155:1599–1611. https://doi.org/10.1016/S0002-9440(10)65476-4
Persidsky Y, Zheng J, Miller D, Gendelman HE (2000) Mononuclear phagocytes mediate blood-brain barrier compromise and neuronal injury during HIV-1-associated dementia. J Leukoc Biol 68:413–422
Persidsky Y, Heilman D, Haorah J et al (2006) Rho-mediated regulation of tight junctions during monocyte migration across the blood-brain barrier in HIV-1 encephalitis (HIVE). Blood 107:4770–4780
Peterson PK, Sharp BM, Gekker G et al (1990) Morphine promotes the growth of HIV-1 in human peripheral blood mononuclear cell cocultures. AIDS 4:869–873
Peterson PK, Gekker G, Schut R et al (1993) Enhancement of HIV-1 replication by opiates and cocaine: the cytokine connection. Adv Exp Med Biol 335:181–188
Peterson PK, Gekker G, Hu S et al (1994) Morphine amplifies HIV-1 expression in chronically infected promonocytes cocultured with human brain cells. J Neuroimmunol 50:167–175. https://doi.org/10.1016/0165-5728(94)90043-4
Polli JW, Jarrett JL, Studenberg SD et al (1999) Role of P-glycoprotein on the CNS disposition of amprenavir (141W94), an HIV protease inhibitor. Pharm Res 16:1206–1212
Price TO, Ercal N, Nakaoke R, Banks WA (2005) HIV-1 viral proteins gp120 and Tat induce oxidative stress in brain endothelial cells. Brain Res 1045:57–63
Pu H, Tian J, András IE et al (2005) HIV-1 Tat protein-induced alterations of ZO-1 expression are mediated by redox-regulated ERK 1/2 activation. J Cereb Blood Flow Metab 25:1325–1335
Pu H, Hayashi K, Andras IE et al (2007) Limited role of COX-2 in HIV Tat-induced alterations of tight junction protein expression and disruption of the blood-brain barrier. Brain Res 1184:333–344. https://doi.org/10.1016/j.brainres.2007.09.063
Ramirez SH, Skuba A, Fan S et al (2012) Activation of cannabinoid receptor 2 attenuates leukocyte – endothelial cell interactions and blood – brain barrier dysfunction under inflammatory conditions. J Neurosci 32:4004–4016. https://doi.org/10.1523/JNEUROSCI.4628-11.2012
Reese MJ, Savina PM, Generaux GT et al (2013) In vitro investigations into the roles of drug transporters and metabolizing enzymes in the disposition and drug interactions of dolutegravir, a HIV integrase inhibitor. Drug Metab Dispos 41:353–361. https://doi.org/10.1124/dmd.112.048918
Reis JM, Dezani AB, Pereira TM et al (2013) Lamivudine permeability study: a comparison between PAMPA, ex vivo and in situ single-pass intestinal perfusion (SPIP) in rat jejunum. Eur J Pharm Sci 48:781–789. https://doi.org/10.1016/j.ejps.2012.12.025
Sacktor N, McDermott MP, Marder K et al (2002) HIV-associated cognitive impairment before and after the advent of combination therapy. J Neuro-Oncol 8:136–142. https://doi.org/10.1080/13550280290049615
Saukkonen JJ, Furfaro S, Mahoney KM et al (1997) In vitro transendothelial migration of blood T lymphocytes from HIV-infected individuals. AIDS 11:1595–1601
Schaefer CP, Arkwright NB, Jacobs LM et al (2018) Chronic morphine exposure potentiates p-glycoprotein trafficking from nuclear reservoirs in cortical rat brain microvessels. PLoS One 13:1–16. https://doi.org/10.1371/journal.pone.0192340
Schier CJ, Marks WD, Paris JJ et al (2017) Selective vulnerability of striatal D2 versus D1 dopamine receptor-expressing medium spiny neurons in HIV-1 Tat transgenic male mice. J Neurosci 37:5758–5769. https://doi.org/10.1523/JNEUROSCI.0622-17.2017
Schwarz JM, Sholar PW, Bilbo SD (2012) Sex differences in microglial colonization of the developing rat brain. J Neurochem 120:948–963. https://doi.org/10.1111/j.1471-4159.2011.07630.x
Shaik N, Giri N, Pan G, Elmquist WF (2007) P-glycoprotein-mediated active efflux of the anti-HIV1 nucleoside abacavir limits cellular accumulation and brain distribution. Drug Metab Dispos 35:2076–2085. https://doi.org/10.1124/dmd.107.017723
Sharma HS, Ali SF (2006) Alterations in blood-brain barrier function by morphine and methamphetamine. Ann N Y Acad Sci 1074:198–224. https://doi.org/10.1196/annals.1369.020
Shiu C, Barbier E, Di Cello F et al (2007) HIV-1 gp120 as well as alcohol affect blood-brain barrier permeability and stress fiber formation: involvement of reactive oxygen species. Alcohol Clin Exp Res 31:130–137. https://doi.org/10.1111/j.1530-0277.2006.00271.x
Stiene-Martin A, Zhou R, Hauser KF (1998) Regional, developmental, and cell cycle-dependent differences in mu, delta, and kappa-opioid receptor expression among cultured mouse astrocytes. Glia 22:249–259. https://doi.org/10.1002/(SICI)1098-1136(199803)22:3<249::AID-GLIA4>3.0.CO;2-0
Strazza M, Pirrone V, Wigdahl B et al (2016) Prolonged morphine exposure induces increased firm adhesion in an in vitro model of the blood–brain barrier. Int J Mol Sci 17. https://doi.org/10.3390/ijms17060916
Tozzi V, Balestra P, Bellagamba R et al (2007) Persistence of neuropsychologic deficits despite long-term highly active antiretroviral therapy in patients with HIV-related neurocognitive impairment: prevalence and risk factors. J Acquir Immune Defic Syndr 45:174–182. https://doi.org/10.1097/QAI.0b013e318157b0f0
Troutman MD, Thakker DR (2003) Rhodamine 123 requires carrier-mediated influx for its activity as a P-glycoprotein substrate in Caco-2 cells. Pharm Res 20:1192–1199
Turchan-Cholewo J, Dimayuga FO, Gupta S et al (2009) Morphine and HIV-Tat increase microglial free radical production and oxidative stress: possible role in cytokine regulation. J Neurochem 108:202–215. https://doi.org/10.1111/j.1471-4159.2008.05756.x.Morphine
Vivithanaporn P, Gill MJ, Power C (2011) Impact of current antiretroviral therapies on neuroAIDS. Expert Rev Anti-Infect Ther 9:371–374
Weiss JM, Nath A, Major EO, Berman JW (1999) HIV-1 Tat induces monocyte chemoattractant protein-1-mediated monocyte transmigration across a model of the human blood-brain barrier and up-regulates CCR5 expression on human monocytes. J Immunol 163:2953–2959
Wen H, Lu Y, Yao H, Buch S (2011) Morphine induces expression of platelet-derived growth factor in human brain microvascular endothelial cells: implication for vascular permeability. PLoS One 6:e21707. https://doi.org/10.1371/journal.pone.0021707
Wiley C, Soontornniyomkij V, Radhakrishnan L et al (1998) Distribution of brain HIV load in AIDS. Brain Pathol 8:277–284. https://doi.org/10.1111/j.1750-3639.1998.tb00153.x
Wilhelm I, Fazakas C, Krizbai IA (2011) In vitro models of the blood-brain barrier. Acta Neurobiol Exp (Wars) 71:113–128
Williams DW, Eugenin EA, Calderon TM, Berman JW (2012) Monocyte maturation, HIV susceptibility, and transmigration across the blood brain barrier are critical in HIV neuropathogenesis. J Leukoc Biol 91:401–415. https://doi.org/10.1189/jlb.0811394
Williams DW, Calderon TM, Lopez L et al (2013) Mechanisms of HIV entry into the CNS: increased sensitivity of HIV infected CD14+CD16+ monocytes to CCL2 and key roles of CCR2, JAM-A, and ALCAM in diapedesis. PLoS One 8:e69270
Williams DW, Anastos K, Morgello S, Berman JW (2015) JAM-A and ALCAM are therapeutic targets to inhibit diapedesis across the BBB of CD14+CD16+ monocytes in HIV-infected individuals. J Leukoc Biol 97:401–412
Winger RC, Koblinski JE, Kanda T et al (2014) Rapid remodeling of tight junctions during paracellular diapedesis in a human model of the blood-brain barrier. J Immunol 193:2427–2437
Wu DT, Woodman SE, Weiss JM et al (2000) Mechanisms of leukocyte trafficking into the CNS. J Neuro-Oncol 6(Suppl 1):S82–S85
Xu R, Feng X, Xie X et al (2012) HIV-1 Tat protein increases the permeability of brain endothelial cells by both inhibiting occludin expression and cleaving occludin via matrix metalloproteinase-9. Brain Res 1436:13–19
Ye Z, Tsao H, Gao H, Brummel CL (2011) Minimizing matrix effects while preserving throughput in LC-MS/MS bioanalysis. Bioanalysis 3:1587–1601. https://doi.org/10.4155/bio.11.141
Yousif S, Saubaméa B, Cisternino S et al (2008) Effect of chronic exposure to morphine on the rat blood-brain barrier: focus on the P-glycoprotein. J Neurochem 107:647–657. https://doi.org/10.1111/j.1471-4159.2008.05647.x
Yousif S, Chaves C, Potin S et al (2012) Induction of P-glycoprotein and Bcrp at the rat blood-brain barrier following a subchronic morphine treatment is mediated through NMDA/COX-2 activation. J Neurochem 123:491–503
Yuen GJ, Weller S, Pakes GE (2008) A review of the pharmacokinetics of abacavir. Clin Pharmacokinet 47:351–371. https://doi.org/10.2165/00003088-200847060-00001
Zhong Y, Smart EJ, Weksler B et al (2008) Caveolin-1 regulates human immunodeficiency virus-1 Tat-induced alterations of tight junction protein expression via modulation of the Ras signaling. J Neurosci 28:7788–7796
Zou S, Fitting S, Hahn YK et al (2011) Morphine potentiates neurodegenerative effects of HIV-1 Tat through actions at mu-opioid receptor-expressing glia. Brain 134:3613–3628. https://doi.org/10.1093/brain/awr281
Acknowledgments
This work was supported by funds from NIH: R21 DA045630 (MPM), R25 MH080661-11 (CRL), R00 DA039791 (JJP), R01 DA044939 and R01 DA034231 (PEK and KFH), K02 DA027374 (KFH), R01 DA018633 (KFH), R01 DA045588 (KFH), P30DA033934-05S1 (MSH) the University of North Carolina at Chapel Hill Center for AIDS Research (CFAR) P30 AI50410 (ADMK), and VCU’s CTSA (UL1TR000058 from the National Center for Advancing Translational Sciences) and the CCTR Endowment Fund of Virginia Commonwealth University (MPM).
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Leibrand, C.R., Paris, J.J., Jones, A.M. et al. HIV-1 Tat and opioids act independently to limit antiretroviral brain concentrations and reduce blood–brain barrier integrity. J. Neurovirol. 25, 560–577 (2019). https://doi.org/10.1007/s13365-019-00757-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13365-019-00757-8