Increased brain P-glycoprotein in morphine tolerant rats

Aquilante, Christina L.; Letrent, Stephen P.; Pollack, Gary M.; Brouwer, Kim L.R.

doi:10.1016/s0024-3205(99)00599-8

Cited by 90 publications

(105 citation statements)

References 11 publications

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“…Data on the effects of chronic exposure to morphine are conflicting [14,15]. In rats chronically treated with morphine, in situ perfusion of sucrose did not allow its penetration into the BBB [15].…”

Section: Discussionmentioning

confidence: 99%

Detection of doxorubicin hydrochloride accumulation in the rat brain after morphine treatment by mass spectrometry

Sardi

Marca

Giovannini

et al. 2010

Cancer Chemother Pharmacol

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Keywords: blood-brain barrier, doxorubicin, morphine, rodent model, mass spectrometry 2 ABSTRACT Purpose: The blood brain barrier discriminates the access of several molecules into the brain. This hampers the use of some drugs, as doxorubicin, potentially active for treatment of brain tumors. We explored the feasibility of active modification of the blood brain barrier protection, by using morphine pretreatment, to allow doxorubicin accumulation into the brain in an animal model. Methods:Rats were pretreated with different doses of intraperitoneal morphine before injection of doxorubicin (12 mg/kg). Quantitative analysis of doxorubicin was performed by mass spectrometry.Acute hearth and kidney damage was analyzed by measuring doxorubicin accumulation, LDH activity and malondialdehyde plasma levels. Results: The concentration of doxorubicin was significantly higher in all brain areas of rats pretreated with morphine than in control tissues (P <0.001). This was evident only at therapeutic morphine dose (10 mg/kg, three times over 24 hours), while lower doses (2.5 and 5 mg/kg) were not associated with doxorubicin accumulation.Pretreatment with morphine did not induce an elevation of LDH activity or of lipid peroxidation compared to controls. Conclusion: Our data suggest that morphine pre-treatment is able to allow doxorubicin penetration inside the brain, by modulating the blood-brain barrier. This is not associated with acute cardiac or renal toxicity. These preliminary results will enable us to generate novel therapeutic approaches to refractory or recurrent brain tumors, and might be useful in other human diseases of the central nervous system in which molecules usually stopped by the blood brain barrier may have a therapeutic impact.3

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Section: Discussionmentioning

confidence: 99%

Detection of doxorubicin hydrochloride accumulation in the rat brain after morphine treatment by mass spectrometry

Sardi

Marca

Giovannini

et al. 2010

Cancer Chemother Pharmacol

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“…Oxycodone-and saline-treated rats were sacrificed by decapitation and intestine, liver, kidney, and brain tissues were isolated and homogenized according to the procedure described elsewhere. 16 Briefly, tissues were removed, rinsed in 4°C isotonic phosphate buffered saline, and homogenized in hypotonic lysis buffer (10 mM Tris HCl, 10 mM NaCl, 10 μg/mL leupeptin, 10 μg/mL aprotinin, and 1 mM phenylmethylsulphonyl fluoride, pH 7.4). Tissue homogenates were centrifuged at 3000×g (4°C) for 15 min to remove nuclear debris and particulate matter.…”

Section: Determination Of the Level Of Expression Of P-gp By Western mentioning

confidence: 99%

“…6 Brain P-gp expression in Sprague Dawley rats was approximately twofold higher in morphine tolerant rats compared to saline control rats based on Western blot analysis. 16 Also, the brain uptake levels of fentanyl, loperamide, meperidine, methadone, morphine, deltorphin II, DPDPE, naltrindole, SNC 121, bremazocine, and U-69593 were determined in mdr1a (+/+) and mdr1a (−/−) mice. The differences in brain uptake between P-gp competent and P-gp deficient mice ranged from no detectable effect (meperidine) to ≥ eightfold increase in uptake (DPDPE, loperamide, and SNC 121).…”

Section: Introductionmentioning

confidence: 99%

“…Oxycodone has been used effectively for over 90 years, but unlike other opioid agonists little is known about its P-gp affinity status (substrate, inducer, or inhibitor). Chronic administration of morphine and other P-gp substrates, e.g., cyclosporin A and dexamethasone resulted in upregulation of P-gp, 16,18 whether P-gp is upregulated upon repeated administration of oxycodone is yet to be elucidated. For the management of cancer, oxycodone is usually coadministered with many chemotherapeutic agents, the majority of these agents are P-gp substrates.…”

Section: Introductionmentioning

confidence: 99%

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Oxycodone induces overexpression of P‐glycoprotein (ABCB1) and affects paclitaxel's tissue distribution in Sprague Dawley rats

Hassan

Myers

Lee

et al. 2007

Journal of Pharmaceutical Sciences

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Previous studies suggest that P-glycoprotein (P-gp) modulates the PK/PD of many compounds including opioid agonists and chemotherapeutic agents. The objective of this study was to assess the P-gp affinity status of oxycodone, the P-gp expression, and the paclitaxel's tissue distribution in oxycodone-treated rats. P-gp ATPase assay, Caco-2 transepithelial permeability studies, and mdr1a/b (−/−) mice were used to assess the P-gp affinity status of oxycodone. P-gp expression was determined by Western blot analysis while [ 14 C] paclitaxel's distributions in the liver, kidney, brain, and plasma tissues were determined by liquid scintillation counter. Oxycodone stimulated the P-gp ATPase activity in a concentration-dependant manner. The Caco-2 secretory transport of oxycodone was reduced from 3.64 ×10 −5 to 1.96 × 10 −5 cm/s (p <0.05) upon preincubation with the P-gp inhibitor, verapamil. The brain levels of oxycodone in mdr1a/b (+/+) were not detectable (<15 ng/mL) while in mdr1a/b (−/−) the average levels were 115 ± 39 ng/mL. The P-gp protein levels were increased by 1.3-4.0 folds while paclitaxel's tissue distributions were decreased by 38-90% (p <0.05) in oxycodone-treated rats. These findings display that oxycodone is a P-gp substrate, induces overexpression of P-gp, and affects paclitaxel's tissue distribution in a manner that may influence its chemotherapeutic activity.

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“…[4][5][6][7][8] Aquilante et al reported that repeated morphine administration caused a two-fold increase in the level of P-glycoprotein in the rat brain associated with a decrease in the antinociceptive effects. 9) King et al also reported that an antisense-oligo against mdr1a suppressed the development of antinociceptive tolerance to intracerebroventricularly administered morphine. 10) Those results suggest that P-glycoprotein at the brain barrier is involved in the development of morphine tolerance.…”

mentioning

confidence: 98%

Effects of Repeated Morphine Treatment on the Antinociceptive Effects, Intestinal Absorption, and Efflux from Intestinal Epithelial Cells of Morphine

Okura

Ozawa

Ibe

et al. 2009

Biological & Pharmaceutical Bulletin

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The present study was conducted to investigate the effects of repeated treatment with morphine on the drug's antinociceptive effects, intestinal absorption, and transepithelial transport. The antinociceptive effects of morphine in rats were markedly decreased after repeated oral administration of the drug for 5 d, indicating the development of tolerance. In the morphine-tolerant rats, intestinal absorption of morphine was determined using the in situ loop method. Absorption of morphine from the jejunum was significantly decreased after repeated administration. The permeability of human intestinal epithelial Caco-2 cells was increased in the efflux direction after repeated treatment. The repeated administration of morphine also reduced the cellular accumulation and efflux of P-glycoprotein substrates ([ 3 H]vincristine and rhodamine123) from Caco-2 cells, suggesting that it enhances P-glycoprotein-mediated efflux in Caco-2 cells. These results suggest that repeated use enhances the efflux of morphine in the epithelial cells of the small intestine, subsequently decreasing its intestinal absorption.

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Increased brain P-glycoprotein in morphine tolerant rats

Cited by 90 publications

References 11 publications

Detection of doxorubicin hydrochloride accumulation in the rat brain after morphine treatment by mass spectrometry

Detection of doxorubicin hydrochloride accumulation in the rat brain after morphine treatment by mass spectrometry

Oxycodone induces overexpression of P‐glycoprotein (ABCB1) and affects paclitaxel's tissue distribution in Sprague Dawley rats

Effects of Repeated Morphine Treatment on the Antinociceptive Effects, Intestinal Absorption, and Efflux from Intestinal Epithelial Cells of Morphine

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