Abstract
Cytochrome P450 2D (CYP2D) metabolizes codeine to morphine, a step required for codeine analgesia. However lower morphine permeability across the blood‐brain barrier, as well as exportation of morphine, suggest that after codeine the initial morphine in the brain, and resulting analgesia, may be due to brain CYP2D activation. Higher brain, but not liver, CYP2D6 is found in smokers, and 7‐day nicotine treatment induces rat brain, but not liver, CYP2D. We hypothesized that inducing rat‐brain CYP2D would increase the CNS CYP2D‐mediated activation of codeine to morphine resulting in increased analgesia, despite first‐pass metabolism, which could be blocked by inhibition of brain CYP2D. Codeine (20mg/kg ip) analgesia was tested: compared to pretreatment with vehicle, 7‐day nicotine (1mg/kg sc, brain CYP2D inducer) increased analgesia (1.59, AUC0‐30min fold change vs. vehicle; p<0.001), propranolol (20 μg in 4 μl icv, brain CYP2D inhibitor) decreased analgesia (0.56; p<0.05), and co‐pretreatment was similar to vehicle (1.23; p>0.1). 7‐day nicotine increased and propranolol decreased brain, but not plasma, morphine levels; analgesia correlated with brain (p<0.02), but not plasma (p>0.4), morphine levels at 15 min after codeine. Pretreatments (alone or together) had no effect on baseline nociception or morphine (3.5mg/kg ip) analgesia. Thus, variation in brain CYP2D activity may contribute to clinically relevant differences in individual response to centrally acting CYP2D substrates. Individuals exposed to nicotine may have increased brain metabolism contributing to altered drug efficacy and abuse liability.Funding: CIHR and the CAMH Foundation
Published Version
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