Brain CYP2D alters orally administered oxycodone induced conditioned place preference in rats

Oxycodone is an opioid analgesic metabolized by the CYP2D enzyme to oxymorphone. We investigated in rats the impact of CYP2D metabolism in the brain on oxycodone-induced reward and aversion, assessed by conditioned place preference (CPP). During conditioning rats were confined to one compartment for 60 minutes after gavage with oxycodone (or oxymorphone) or with water; treatment and compartments were alternated daily for six days. Rats then underwent 60 minutes of posttests for five days where CPP was assessed. Pretreatments with the CYP2D inhibitor propranolol, or vehicle, injected intracerebroventricularly 24 hours - prior to first and third of six conditioning sessions blunted CPP and with a trend for increased aversion to the oxycodone paired compartment. Pretreatment with the brain CYP2D enzyme inducer nicotine, for 12 days prior to oxycodone conditioning, did not change CPP to oxycodone but tended to reduced aversion to oxycodone paired compartment. Oral oxymorphone induced a CPP with no observed aversion; it was unaffected by CYP2D inhibitor pretreatment. Together this indicates that oral oxycodone and oral oxymorphone both induce CPP. Inhibiting brain CYP2D, previously shown to reduce the relative concentrations of oxycodone to oxymorphone, reduces CPP and tended to increase aversion suggesting that variation in CYP2D activity in the brain could be a source of interindividual differences in oxycodone induced reward and abuse liability.