Abstract
Purpose. Previous studies have suggested that P-glycoprotein (P-gp)modulates opioid antinociception for selected μ-and δ-agonists. Thisstudy was undertaken to assess morphine antinociception in micelacking the mdr1a gene for expression of P-gp in the CNS.
Methods. Morphine (n = 4–5/group) was administered as a single s.c.dose to mdr1a(−/−) mice (3–5 mg/kg) or wild-type FVB controls(8–10 mg/kg). Tail-flick response to radiant heat, expressed as percentof maximum response (%MPR), was used to determine theantinociceptive effect of morphine. Concentrations in serum, brain tissue, andspinal cord samples obtained immediately after the tail-flick test weredetermined by HPLC with fluorescence detection. Parallel experimentswith R(+)-verapamil, a chemical inhibitor of P-gp, also were performedto further investigate the effect of P-gp on morphine-associatedantinociception.
Results. Morphine-associated antinociception was increasedsignificantly in the mdr1a(−/−) mice. The ED50 for morphine was > 2-foldlower in mdr1a(−/−) (3.8 ± 0.2 mg/kg) compared to FVB (8.8 ±0.2 mg/kg) mice. However, the EC;i5;i0 derived from the brain tissuewas similar between the two mouse strains (295 ng/g vs. 371 ng/g).Pretreatment with R(+)-verapamil produced changes similar to thoseobserved in gene-deficient mice. P-gp does not appear to affectmorphine distribution between spinal cord and blood, as the spinalcord:serum morphine concentration ratio was similar betweengene-deficient and wild-type mice (0.47 ± 0.03 vs. 0.56 ± 0.04, p > 0.05).
Conclusions. The results of this study are consistent with thehypothesis that P-gp attenuates the antinociceptive action of morphine bylimiting the brain:blood partitioning of the opioid.
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REFERENCES
C. R. Leveille-Webster and I. M. Arias. The biology of P-glycoproteins. J. Membrane Biol. 143:89–102 (1995).
C. Cordon-Cardo, J. P. O'Brien, J. Boccia, D. Casals, J. R. Bertino, and M. R. Melamed. Expression of multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J. Histochem. Cytochem. 38:1277–1287 (1990).
F. Thiebaut, T. Tsuruo, H. Hamada, M. M. Gottesman, I. Pastan, and M. C. Willingham. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc. Natl. Acad. Sci. USA 84:7735–7738 (1987).
A. H. Schinkel, E. Wagenaar, C. A. A. M. Mol, and L. V. Deemter. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J. Clin. Invest. 97:2517–2524 (1996).
H. M. Bender and J. Dasenbrock. Brain concentrations of asimadoline in mice: the influence of coadministration of various P-glycoprotein substrates. Int. J. Clin. Pharmacol. Ther. 36:76–79 (1998).
S. P. Letrent, G. M. Pollack, K. R. Brouwer, and K. L. R. Brouwer. Effect of GF120918, a potent P-glycoprotein inhibitor, on morphine pharmacokinetics and pharmacodynamics in the rat. Pharm. Res. 15:599–605 (1998).
S. P. Letrent, G. M. Pollack, K. R. Brouwer, and K. L. R. Brouwer. Effects of a potent and specific P-glycoprotein inhibitor on the blood-brain barrier distribution and antinociceptive effect of morphine in the rat. Drug Metab. Dispos. 27:827–833 (1999).
S. P. Letrent, J. W. Polli, J. E. Humphreys, G. M. Pollack, K. R. Brouwer, and K. L. R. Brouwer. P-glycoprotein-mediated transport of morphine in brain capillary endothelial cells. Biochem. Pharmacol. 58:951–957 (1999).
R. Callaghan and J. R. Riordan. Synthetic and natural opiates interact with P-glycoprotein in multidrug-resistant cells. J. Biol. Chem. 268:16059–16064 (1993).
A. H. Schinkel, E. Wagenaar, L. V. Deemter, C. A. A. M. Mol, and P. Borst. Absence of the mdr1a(¶ /¶ ) P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J. Clin. Invest. 96:1698–1705 (1995).
C. Chen and G. M. Pollack. Development of a capillary zone electrophoresis assay to examine the disposition of [D-pen2,5]enkephalin in rats. J. Chromatogr. B Biomed. Appl. 681:363–373 1996).
C. Chen and G. M. Pollack. Blood-brain disposition and antinociceptive effects of [D-penicillamine2,5] enkephalin in the mouse. J. Pharmacol. Exp. Ther. 283:1151–1157 (1997).
C. Chen and G. M. Pollack. Extensive biliary excretion of the model opioid peptide [D-pen2,5]enkephalin in rats. Pharm. Res. 14:345–350 (1997).
C. Chen and G. M. Pollack. Enhanced antinociception of the model opioid peptide [D-penicillamine2,5]enkephalin by P-glycoprotein modulation. Pharm. Res. 16:296–302 (1999).
C. Chen and G. M. Pollack. Altered disposition and antinociception of [D-penicillamine2,5]enkephalin in the mdr1a(¶ /¶ ) gene-deficient mice. J. Pharmacol. Exp. Ther. 287:545–552 (1998).
T. Tsuruo, H. Iida, S. Tsukagoshi, and Y. Sakurai. Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res. 41:1967–1972 (1981).
R. F. Venn and A. Michalkiewicz. Fast reliable assay for morphine and its metabolites using high-performance liquid chromatography and native fluorescence detection. J. Chromatogr. 525:379–388 (1990).
D. M. C. Ouellet and G. M. Pollack. Biliary excretion and enterohepatic recirculation of morphine-3-glucuronide in rats. Drug Metab. Dispos. 23:478–484 (1995).
C. Stein. Opioids in pain control: Basic and clinical aspects. Cambridge Univesity Press, New York, p.70 (1999).
V. V. Rao, J. L. Dahlheimer, M. E. Bardgett, A. Z. Snyder, R. A. Finch, A. C. Sartorelli, and D. Piwnica-Worms. Choroid plexus epithelial expression of MDR1 P-glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier. PNAS 96:3900–3905 (1999).
H. Echizen, T. Brecht, S. Niedergesass, B. Vogelgesang, and M. Eichelbaum. The effect of dextro-, levo-, and racemic verapamil on atrioventriclar conduction in humans. Am. Heart J. 109:210–217 (1985).
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Zong, J., Pollack, G.M. Morphine Antinociception Is Enhanced in mdr1a Gene-Deficient Mice. Pharm Res 17, 749–753 (2000). https://doi.org/10.1023/A:1007546719287
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DOI: https://doi.org/10.1023/A:1007546719287