Impact of P-glycoprotein at the blood-brain barrier on the uptake of heroin and its main metabolites: behavioral effects and consequences on the transcriptional responses and reinforcing properties

Seleman, Marianne; Chapy, Hélène; Cisternino, Salvatore; Courtin, Cindie; Smirnova, Maria; Schlatter, Joël; Chiadmi, Fouad; Scherrmann, Jean‐Michel; Noble, Florence; Marie-Claire, Cynthia

doi:10.1007/s00213-014-3490-9

Cited by 32 publications

(34 citation statements)

References 53 publications

(54 reference statements)

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“…Neurobiological studies have recently confirmed that the BBB transport rate of drugs of abuse like nicotine, morphine, or cocaine is a critical factor that affects the neurobehavioral plasticity involved in addiction ( Samaha and Robinson, 2005 ; Minogianis et al, 2013 ; Seleman et al, 2014 ). A higher rate of cocaine brain delivery is associated with a greater risk of addiction in rodents ( Minogianis et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Carrier-Mediated Cocaine Transport at the Blood-Brain Barrier as a Putative Mechanism in Addiction Liability

Chapy¹,

Smirnova²,

André³

et al. 2014

International Journal of Neuropsychopharmacology

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Background:The rate of entry of cocaine into the brain is a critical factor that influences neuronal plasticity and the development of cocaine addiction. Until now, passive diffusion has been considered the unique mechanism known by which cocaine crosses the blood-brain barrier.Methods:We reassessed mechanisms of transport of cocaine at the blood-brain barrier using a human cerebral capillary endothelial cell line (hCMEC/D3) and in situ mouse carotid perfusion.Results:Both in vivo and in vitro cocaine transport studies demonstrated the coexistence of a carrier-mediated process with passive diffusion. At pharmacological exposure level, passive diffusion of cocaine accounted for only 22.5% of the total cocaine influx in mice and 5.9% in hCMEC/D3 cells, whereas the carrier-mediated influx rate was 3.4 times greater than its passive diffusion rate in vivo. The functional identification of this carrier-mediated transport demonstrated the involvement of a proton antiporter that shared the properties of the previously characterized clonidine and nicotine transporter. The functionnal characterization suggests that the solute carrier (SLC) transporters Oct (Slc22a1-3), Mate (Slc47a1) and Octn (Slc22a4-5) are not involved in the cocaine transport in vivo and in vitro. Diphenhydramine, heroin, tramadol, cocaethylene, and norcocaine all strongly inhibited cocaine transport, unlike benzoylecgonine. Trans-stimulation studies indicated that diphenhydramine, nicotine, 3,4-methylenedioxyamphetamine (ecstasy) and the cathinone compound 3,4-methylenedioxypyrovalerone (MDPV) were also substrates of the cocaine transporter.Conclusions:Cocaine transport at the BBB involves a proton-antiporter flux that is quantitatively much more important than its passive diffusion. The molecular identification and characterization of this transporter will provide new tools to understand its role in addictive mechanisms.

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Section: Discussionmentioning

confidence: 99%

Carrier-Mediated Cocaine Transport at the Blood-Brain Barrier as a Putative Mechanism in Addiction Liability

Chapy¹,

Smirnova²,

André³

et al. 2014

International Journal of Neuropsychopharmacology

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“…The major difference between oxycodone and morphine is the passage through the blood-brain barrier. Both opioids are equally hydrophilic, yet oxycodone is actively transported through the endothelial cells of the blood-brain barrier in animal models by a cation-proton antiporter [188] six times more than morphine [189]. This unique mechanism produces a concentration of oxycodone three times higher in the brain compared to the blood [190].…”

Section: Oxycodonementioning

confidence: 99%

Are Opioids Effective in Relieving Neuropathic Pain?

Schembri

2018

SN Compr. Clin. Med.

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Neuropathic pain (NP) and its treatment are considered to constitute an unmet need, with a high-multidimensional impact on society and the sufferer. The broad spectrum of opioid analgesics is considered beneficial for acute pain, yet these drugs pose serious controversial issues due to the potential for adverse behavior and a higher chance of tolerance and addiction in long-term use. Opioids like other first-line medications for NP, will not be useful for every patient suffering from chronic NP. However, due to their possible adverse effects, opioids are considered as second-or third-line medications by various guidelines. Therefore, this literature review was conducted to evaluate the status of opioids in NP and to asses if any recent research has shed further evidence on their efficacy or the contrary. The literature reviewed showed that the mechanisms underlying NP, may themselves contribute to the reduced effect of opioids in this condition. Also, various genetic polymorphisms affecting pharmacokinetic and pharmacodynamic factors are discussed, providing further evidence for the variability in opioid response. Although opioids may reduce NP, nociceptive pain tends to be more responsive to opioids compared to NP. Also, opioids seem to be more effective in intermediate term studies of up to 12 weeks and being mostly effective in peripheral NP compared to supraspinal NP and being least effective in central NP. However, there is still no robust evidence that any specific opioid agent is better than any other one for NP, but it is possible that opioids targeting multiple mechanisms may provide benefit. A limitation of many trials is the lack of consideration for the comorbid psychological aspects of NP, which tend to lower opioid analgesia.

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“…Seleman és mtsai a heroinnak és metabolitjainak P-gp kölcsönhatását vizsgálták in situ agyi perfúziós módszer-rel [27]. Ugyanezt a technikát alkalmazták professzor Sugiyama és mtsai aromatázinhibitorok P-gp és BCRP interakciójának vizsgálatára [28].…”

Section: Vizsgálati Módszerekunclassified

Gyógyszertranszporterek szerepe a központi idegrendszerben

Temesszentandrási-Ambrus

Beéry

2016

Orvosi Hetilap

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Bár a vér-agy gát jelenlétét az emlősszervezetekben már a XX. század elején felismerték, pontos szerkezetét, illetve a benne található gyógyszertranszporter fehérjéket csak az utóbbi évtizedekben azonosították. A központi idegrendszer védelmét biztosító ATP-kötő kazettatranszporter pumpafehérjék mellett fontos szerepet játszanak az idegrendszer működésében a solute carrier transzporterek is, amelyek a táplálék-és energiaellátást biztosítják, illetve a metabolizmus során "eltakarító" funkciót is betöltenek. Az összefoglaló közlemény áttekintést ad az idegrendszerben előforduló főbb transzporter fehérjetípusokról, sejttípusonkénti lokalizációjukról, illetve a vizsgálatukra szolgáló főbb módszerekről. A közlemény második felében különböző neurodegeneratív betegségek és a patológiájukkal összefüg-gésbe hozható transzporter fehérjék kerülnek bemutatásra. Mindezek fényében olyan új terápiás stratégiák kerülhet-nek a figyelem középpontjába, amelyek a jelenleg gyógyíthatatlan betegségek esetében jelenthetnek majd megoldást. Orv. Hetil., 2016, 157(10), 370-378. Kulcsszavak: membrántranszporterek, vér-agy gát, neurodegeneratív betegségek, központi idegrendszer Role of drug transporters in the central nervous systemAlthough the presence of blood-brain barrier in the mammalian organisms was discovered in the early 1900s, its precise structure and the drug transporter proteins localized in the blood-brain barrier were identified only in the last decades. Beside the ATP-binding cassette transporter proteins responsible for the protection of the brain, the Solute Carrier transporters play also an important role in the function of the central nervous system by its feeding, energy supply and cleaning function during the metabolism. This review provides an overview on the main types of transporters located in the brain, on their localization in different cell types and the main techniques for their investigation. In the second part of this article various neurodegenerative disorders and the pathology-related transporter proteins are presented. In the light of recent experimental results new therapeutic strategies may come into the focus of research for the treatment of disorders currently without effective therapy. Rövidítések Aβ = béta-amiloid protein; ABC = ATP-binding cassette transporter; AIDS = acquired immunodeficiency syndrome; ALS = amyotrophiás lateralsclerosis; ANLSH = astrocyta-neuron laktát sönt hipotézis; ATP = adenozin-trifoszfát; BCRP = breast cancer resistance protein; Caco2 = caucasian colon adenocarcinoma cell line; CSF = cerebrospinal fluid; CTL = kolintranszporter; DAT = dopamintranszporter; EAAT = excitáns aminosav-transzporter; ECF = extracellular fluid; FDA = Food and Drug Administration; GABA = gamma-aminovajsav; GAT = GABA-transzporter; GLAST = glutamát-aszpartát transzporter; GLT = glutamáttranszporter; GLUT = glükóztranszpor-ter; GlyT = glicintranszporter; hCMEC/D3 = human cerebral microvascular endothelial cell line; HIV = human immunodeficiency virus; HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A; K...

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Impact of P-glycoprotein at the blood-brain barrier on the uptake of heroin and its main metabolites: behavioral effects and consequences on the transcriptional responses and reinforcing properties

Cited by 32 publications

References 53 publications

Carrier-Mediated Cocaine Transport at the Blood-Brain Barrier as a Putative Mechanism in Addiction Liability

Carrier-Mediated Cocaine Transport at the Blood-Brain Barrier as a Putative Mechanism in Addiction Liability

Are Opioids Effective in Relieving Neuropathic Pain?

Gyógyszertranszporterek szerepe a központi idegrendszerben

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