A non-rewarding, non-aversive buprenorphine/naltrexone combination attenuates drug-primed reinstatement to cocaine and morphine in rats in a conditioned place preference paradigm

Concurrent use of cocaine and heroin is a major public health issue with no effective relapse prevention treatment currently available. To this purpose, a combination of buprenorphine and naltrexone, a mixed very‐low efficacy mu‐opioid receptor agonist/kappa‐opioid receptor antagonist/nociceptin receptor agonist, was investigated. The tail‐withdrawal and the conditioned place preference (CPP) assays in adult Sprague Dawley rats were used to show that naltrexone dose‐dependently blocked the mu‐opioid receptor agonism of buprenorphine. Furthermore, in the CPP assay, a combination of 0.3 mg/kg buprenorphine and 3.0 mg/kg naltrexone was aversive. A combination of 0.3 mg/kg buprenorphine and 1.0 mg/kg naltrexone was neither rewarding nor aversive, but still possessed mu‐opioid receptor antagonist properties. In the CPP extinction and reinstatement method, a combination of 0.3 mg/kg buprenorphine and 1.0 mg/kg naltrexone completely blocked drug‐primed reinstatement in cocaine‐conditioned rats (conditioned with 3 mg/kg cocaine, drug prime was 3 mg/kg cocaine) and attenuated drug‐primed reinstatement in morphine‐conditioned rats (conditioned with 5 mg/kg morphine, drug prime was 1.25 mg/kg morphine). These data add to the growing evidence that a buprenorphine/naltrexone combination may be protective against relapse in a polydrug abuse situation. Clinical trials have suggested that a combination of buprenorphine and naltrexone might be effective as a treatment for opioid and cocaine addiction. In this rat study we find a ratio of buprenorphine/naltrexone that is neither aversive nor rewarding, and that attenuated drug‐primed reinstatement to conditioned place preference to both morphine and cocaine. Further in vitro and in vivo studies characterised mu‐opioid receptor occupancy by this drug combination.