Nicotine Increases Codeine Analgesia Through the Induction of Brain CYP2D and Central Activation of Codeine to Morphine

Abstract

CYP2D metabolically activates codeine to morphine, which is required for codeine analgesia. Permeability across the blood-brain barrier, and active efflux, suggests that initial morphine in the brain after codeine is due to brain CYP2D metabolism. Human CYP2D is higher in the brains, but not in the livers, of smokers and 7-day nicotine treatment induces rat brain, but not hepatic, CYP2D. The role of nicotine-induced rat brain CYP2D in the central metabolic activation of peripherally administered codeine and resulting analgesia was investigated. Rats received 7-day nicotine (1 mg/kg subcutaneously) and/or a single propranolol (CYP2D mechanism-based inhibitor; 20 μg intracerebroventricularly) pretreatment, and then were tested for analgesia and drug levels following codeine (20 mg/kg intraperitoneally) or morphine (3.5 mg/kg intraperitoneally), matched for peak analgesia. Nicotine increased codeine analgesia (1.59X AUC(0-30 min) vs vehicle; p<0.001), while propranolol decreased analgesia (0.56X; p<0.05); co-pretreatment was similar to vehicle controls (1.23X; p>0.1). Nicotine increased, while propranolol decreased, brain, but not plasma, morphine levels, and analgesia correlated with brain (p<0.02), but not plasma (p>0.4), morphine levels after codeine. Pretreatments did not alter baseline or morphine analgesia. Here we show that brain CYP2D alters drug response despite the presence of substantial first-pass metabolism of codeine and further that nicotine induction of brain CYP2D increases codeine response in vivo. Thus variation in brain CYP2D activity, due to genetics or environment, may contribute to individual differences in response to centrally acting substrates. Exposure to nicotine may increase central drug metabolism, not detected peripherally, contributing to altered drug efficacy, onset time, and/or abuse liability.

Nicotine pre-treatment reduces sensitivity to the interoceptive stimulus effects of commonly abused drugs as assessed with taste conditioning paradigms

“…For instance, nicotine could be reducing sensitivity to these stimulus properties of each of the tested drugs at their receptor subtypes critical for their ability to induce CTR (Tuesta et al, 2011) through either impacting the pharmacodynamics or kinetics of drug administration. Importantly, nicotine does not appear to impact the kinetics of morphine (McMillan and Tyndale, 2015) or cocaine (Kouri et al, 2001) and therefore increased metabolism is likely not responsible for the impact of nicotine on these two drugs; interactions between nicotine and ethanol kinetics are more equivocal (Hisaoka and Levy, 1985; Kouri et al, 2004; Schoedel and Tyndale, 2003; Yue et al, 2009). Altering any of these properties, even slightly, could significantly impact conditioning.…”

Assessment of sexual behaviour and fertility indices in male rabbits following chronic codeine use

“…The 4 mg/kg dose was based on the adult human equivalent dose of 1.2 mg/kg daily in three divided doses using the FDA draft guidelines (Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, ), while the 10 mg/kg dose was chosen from dose‐response curves to obtain a submaximal peak dose from our pilot study. This is similar to the dose reported by Mcmillan & Tyndale ().…”

“Target-Site” Drug Metabolism and Transport

“…Smokers have higher CYP2D6 protein in the basal ganglia and cerebellar regions, and chronic nicotine treatment can increase CYP2D6 expression in monkeys (Mann et al, 2008) and CYP2D1 expression in rats . Thus, it is likely that induced levels of CYP2D within the brain will increase the formation rate of morphine and subsequently increase analgesiawhich was recently confirmed (McMillan and Tyndale, 2015).…”