Pharmaceutical Research

, Volume 17, Issue 6, pp 749–753

Morphine Antinociception Is Enhanced in mdr1a Gene-Deficient Mice

Article

DOI: 10.1023/A:1007546719287

Cite this article as:
Zong, J. & Pollack, G.M. Pharm Res (2000) 17: 749. doi:10.1023/A:1007546719287

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.

P-glycoproteinmdr1a(−/−) micemorphineantinociceptionblood—brain barrierpharmacodynamics

Copyright information

© Plenum Publishing Corporation 2000

Authors and Affiliations

  1. 1.Division of Drug Delivery and Disposition, School of PharmacyUniversity of North Carolina at Chapel HillChapel Hill
  2. 2.Division of Drug Delivery and Disposition, School of PharmacyUniversity of North Carolina at Chapel HillChapel Hill