Inhibition of CYP2D enzymes in the brain reduces oral oxycodone-induced conditioned place preference in rats

Aim: Oxycodone is a widely used and misused opioid analgesic. CYP2D metabolizes oxycodone; our aim was to investigate brain CYP2D inhibitor pretreatment on oxycodone reward using conditioned place preference (CPP).

Methods: Male Wistar Han rats were habituated to CPP apparatus for 30 minutes. The next day, rats were allowed to explore the apparatus for 60 minutes. The following day, and mid-way through conditioning, rats were pretreated ICV with the CYP2D inhibitor propranolol or vehicle. The next day rats received oxycodone (3 mg/kg) or water via gavage and were confined to one compartment for 60 minutes. The treatment and compartment were alternated daily. Rats then received two 60 min drug-free post-tests and a state-dependent test (oxycodone 3 mg/kg) over three days. CPP was defined as an increase in time in the oxycodone versus water-paired compartment.

Results: In both experiments, little consistent CPP was observed in post-test 1. However, in experiment 1, in post-test 2, and the state-dependent tests, there was CPP in the vehicle-pretreated rats (p=0.047 and p=0.038) but not in the inhibitor-pretreated (p=0.742 and p=0.283) rats. Likewise, in experiment 2, in the post-test 2 and state-dependent tests, there was CPP in the vehicle-pretreated rats (p=0.021 and p=0.001) but not in inhibitor-pretreated (p=0.440 and p=0.387) rats. A trend for CPP (p=0.058) persisted in the vehicle-pretreated rats but not the inhibitor-pretreated rats for 22 days.

Conclusion: The CYP2D inhibitor blunts oral oxycodone-induced CPP, indicating that variations in the brain CYP2D metabolism of oxycodone may contribute to inter-individual differences in oxycodone misuse liability.