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

Todd M. Hillhouse, Keith M. Olson, James E. Hallahan, Lauren G. Rysztak, Bryan F. Sears, Claire Meurice, Mehrnoosh Ostovar, Peyton O. Koppenhaver, Joshua L. West, Emily M. Jutkiewicz, Stephen M. Husbands, John R. Traynor

Research output: Contribution to journalArticlepeer-review

5 Citations (SciVal)

Abstract

There are no Food and Drug Administration-approved medications for cocaine use disorder, including relapse. The μ-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. Buprenorphine's partial agonist and antagonist activity at the nociception receptor (NOPr) and κ-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 analogs, BU10119 and BU12004, in assays for antinociception and for cocaineand 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 δ-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 analogs lacking MOPr agonism with increased NOPr agonism for relapse prevention to cocaine addiction.

Original languageEnglish
Pages (from-to)287-299
Number of pages13
JournalJournal of Pharmacology and Experimental Therapeutics
Volume378
Issue number3
Early online date22 Sep 2021
DOIs
Publication statusPublished - 30 Sep 2021

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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