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

Abstract

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.

• Authors: Marsida Kallupi, Qianwei Shen, Giordano de Guglielmo, Dennis Yasuda, V Blair Journigan, Nurulain T Zaveri, Roberto Ciccocioppo
• Journal: Addiction biology (Addict Biol) Vol. 23 Issue 2 Pg. 585-595 (03 2018) ISSN: 1369-1600 [Electronic] United States
• PMID: 28635181 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2017 Society for the Study of Addiction.

Chemical References

• 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

Topics

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