Buprenorphine requires concomitant activation of NOP and MOP receptors to reduce cocaine consumption

Addict Biol. 2018 Mar;23(2):585-595. doi: 10.1111/adb.12513. Epub 2017 Jun 21.


Buprenorphine's clinical use is approved for the treatment of heroin addiction; however, evidence supporting its efficacy in cocaine abuse also exists. While for heroin it has been demonstrated that the effect of buprenorphine is mediated by its ability to activate μ-opioid peptide receptor (MOP) receptors, the mechanism through which it attenuates cocaine intake remains elusive. We explored this mechanism using operant models where rodents were trained to chronically self-administer cocaine for 2 hours daily. Buprenorphine (0.3, 1.0 and 3.0 mg/kg) given intraperitoneally 90 minutes before access to cocaine significantly and dose dependently reduced its intake. Pre-treatment with naltrexone or with the selective nociceptin/orphanin FQ peptide (NOP) antagonist SB-612111 did not prevent buprenorphine-induced reduction of cocaine intake. However, when naltrexone and SB-612111 were combined, the effect of buprenorphine on cocaine was completely prevented. To confirm that co-activation of MOP and NOP receptors is the underlying mechanism through which buprenorphine reduces cocaine intake, three compounds, namely, AT-034, AT-201 and AT-202, with a range of affinity and intrinsic activity profiles for MOP and NOP receptors, but weak ability for kappa-opioid peptide receptor (KOP) transmission, were tested. Consistent with our hypothesis based on buprenorphine's effects, results demonstrated that AT-034 and AT-201, which co-activate MOP and NOP receptors, reduced cocaine self-administration like buprenorphine. AT-202, which selectively stimulates NOP receptors, was not effective. Together, these data demonstrate that for buprenorphine, co-activation of MOP and NOP receptors is essential to reduce cocaine consumption. These results open new vistas on the treatment of cocaine addiction by developing compounds with mixed MOP/NOP agonist properties.

Keywords: MOP and NOP receptors; addiction; buprenorphine; cocaine; self-administration.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Buprenorphine / pharmacology*
  • Cocaine / administration & dosage*
  • Conditioning, Operant
  • Cycloheptanes / pharmacology
  • Dopamine Uptake Inhibitors / administration & dosage*
  • Naltrexone / pharmacology
  • Narcotic Antagonists / pharmacology*
  • Nociceptin Receptor
  • Piperidines / pharmacology
  • Rats
  • Receptors, Opioid / drug effects*
  • Receptors, Opioid, mu / drug effects*
  • Self Administration


  • Cycloheptanes
  • Dopamine Uptake Inhibitors
  • Narcotic Antagonists
  • Piperidines
  • Receptors, Opioid
  • Receptors, Opioid, mu
  • cis-1-methyl-7-((4-(2,6-dichlorophenyl)piperidin-1-yl)methyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol
  • Buprenorphine
  • Naltrexone
  • Cocaine
  • Nociceptin Receptor
  • Oprl protein, rat