The buprenorphine analogue BU10119 attenuates drug-primed and stress-induced cocaine reinstatement in mice.

There are no Food and Drug Administration-approved medications for cocaine use disorder, including relapse. The mu-opioid receptor (MOPr) partial agonist buprenorphine, alone or in combination with naltrexone, has been shown to reduce cocaine positive urine tests and cocaine seeking in rodents. However, there are concerns over the abuse liability of buprenorphine. Buprenorphine9s partial agonist and antagonist activity at the nociception-receptor (NOPr) and kappa-opioid receptor (KOPr), respectively, may contribute to its ability to inhibit cocaine seeking. Thus, we hypothesized that a buprenorphine derivative that exhibits antagonist activity at MOPr and KOPr with enhanced agonist activity at the NOPr could provide a more effective treatment. Here we compare the pharmacology of buprenorphine, and two analogues BU10119, and BU12004, in assays for antinociception, and for cocaine- and stress-primed reinstatement in the conditioned place preference paradigm. In vitro and in vivo assays showed that BU10119 acts as an antagonist at MOPr, KOPr, and delta-opioid receptor (DOPr) and a partial agonist at NOPr, whereas BU12004 showed MOPr partial agonist activity, and DOPr, KOPr and NOPr antagonism. BU10119 and buprenorphine, but not BU12004 lessened cocaine-primed reinstatement. In contrast, BU10119, BU12004, and buprenorphine blocked stress-primed reinstatement. The selective NOPr agonist SCH221510, but not naloxone, decreased cocaine-primed reinstatement. Together, these findings are consistent with the concept that NOPr agonism contributes to the ability of BU10119 and buprenorphine to attenuate reinstatement of cocaine conditioned place preference in mice. The findings support the development of buprenorphine analogues lacking MOPr agonism with increased NOPr agonism for relapse prevention to cocaine addiction. Significance Statement There are no FDA-approved medications for cocaine use disorder. Buprenorphine has shown promise as a treatment for cocaine relapse prevention; however, there are concerns over the abuse liability of buprenorphine. Here we show a buprenorphine analogue BU10119, which lacks mu-opioid receptor agonism, inhibits cocaine-primed and stress-primed reinstatement in a conditioned place-preference paradigm. The results suggest the development of BU10119 for the management of relapse to cocaine-seeking.