Morphine antinociception is enhanced in mdr1a gene-deficient mice

Purpose. Previous studies have suggested that P-glycoprotein (P-gp) modulates opioid antinociception for selected μ-and δ-agonists. This study was undertaken to assess morphine antinociception in mice lacking 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 percent of maximum response (%MPR), was used to determine the antinociceptive effect of morphine. Concentrations in serum, brain tissue, and spinal cord samples obtained immediately after the tail-flick test were determined by HPLC with fluorescence detection. Parallel experiments with R(+)-verapamil, a chemical inhibitor of P-gp, also were performed to further investigate the effect of P-gp on morphine-associated antinociception. Results. Morphine-associated antinociception was increased significantly in the mdr1a(-/-) mice. The ED₅₀ for morphine was > 2-fold lower in mdr1a(-/-) (3.8 ± 0.2 mg/kg) compared to FVB (8.8 ± 0.2 mg/kg) mice. However, the EC₅₀ derived from the brain tissue was similar between the two mouse strains (295 ng/g vs. 371 ng/g). Pretreatment with R(+)-verapamil produced changes similar to those observed in gene-deficient mice. P-gp does not appear to affect morphine distribution between spinal cord and blood, as the spinal cord:serum morphine concentration ratio was similar between gene-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 the hypothesis that P-gp attenuates the antinociceptive action of morphine by limiting the brain:blood partitioning of the opioid.