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


OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Tzschentke
Thomas M
TM
Department of Pharmacology, Grünenthal GmbH, 52099, Aachen, Germany. thomas.tzschentke@grunenthal.de
D000818:Animals; D002047:Buprenorphine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009270:Naloxone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists; D009294:Narcotics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors; D013997:Time Factors; D000094942:Nociceptin Receptor
D002047:Buprenorphine; D009270:Naloxone; D009271:Naltrexone; D009292:Narcotic Antagonists; D009294:Narcotics; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D000094942:Nociceptin Receptor; C058380:naloxone benzoylhydrazone; C051844:norbinaltorphimine; C055382:naltrindole; C000722285:Oprl1 protein, rat