Reassessment of buprenorphine in conditioned place preference: temporal and pharmacological considerations

Abstract

Buprenorphine is widely used as an analgesic drug and it is also increasingly considered for maintenance and detoxification of heroin addicts. It is a potent micro -receptor partial agonist with a long duration of action. An inverted U-shaped dose-effect curve for buprenorphine conditioned place preference (CPP) has been shown previously. We re-evaluated the CPP effects of buprenorphine by taking into account the particular kinetic properties of the drug in the design of the experiments. An unbiased CPP procedure with different wash-out periods was used to investigate a possible influence of the long duration of action of buprenorphine on the outcome of the experiment. Following a standard procedure (drug and vehicle conditioning on alternating days), the inverted U-shaped dose-effect curve was reproduced (no CPP at 0.01 mg/kg, significant CPP at 0.1 and 1.0 mg/kg, and no CPP at 3.16 and 10 mg/kg, IP). However, when there was a 48 h interval between drug and vehicle conditioning, there was a clear tendency towards CPP for the two highest doses, and when there was a 72-h interval between drug and vehicle conditioning, significant CPP was seen. Naloxone (0.215 mg/kg SC), haloperidol (0.215 mg/kg IP) and U-50488 (1.0 mg/kg SC) blocked buprenorphine (1.0 mg/kg) CPP. Buprenorphine CPP was also blocked by coadministration of naltrindole (3.16 mg/kg IP), nor-binaltorphimine (4.64 mg/kg SC), and naloxonebenzoylhydrazone (0.464 mg/kg SC). However, the data suggest that blockade by the three latter drugs was due to state-dependency effects. Buprenorphine at doses of 1.0 mg/kg and higher also produced locomotor sensitization across the 3 drug conditioning days. The sensitization produced by 1.0 mg/kg buprenorphine was blocked by haloperidol and U-50488, but not by naloxone, naltrindole, nor-binaltorphimine, and naloxonebenzoylhydrazone. The present results suggest that the reported lack of CPP effects at high doses of buprenorphine may be due to factors in the experimental design, resulting in a carry-over effect from drug- to vehicle conditioning. They also suggest that buprenorphine, like other opiates, produces its CPP effects via micro -receptors, although kappa-antagonistic mechanisms also appear to be involved. The implications of these findings for the safety of buprenorphine for human use are discussed.