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.