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 S prague D awley 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.