Cocaine addiction is a widespread psychiatric condition still waiting for approved efficacious medications. Previous studies suggested that simultaneous activation of nociceptin opioid (NOP) and mu opioid (MOP) receptors could be a successful strategy to treat cocaine addiction, but the paucity of molecules co-activating both receptors with comparable potency has hampered this line of research. Cebranopadol is a non-selective opioid agonist that at nanomolar concentration activates both NOP and MOP receptors and that recently reached phase-III clinical trials for cancer pain treatment. Here, we tested the effect of cebranopadol on cocaine self-administration (SA) in the rat. We found that under a fixed-ratio-5 schedule of reinforcement, cebranopadol (25 and 50 µg/kg) decreased cocaine but not saccharin SA, indicating a specific inhibition of psychostimulant consumption. In addition, cebranopadol (50 µg/kg) decreased the motivation for cocaine as detected by reduction of the break point measured in a progressive-ratio paradigm. Next, we found that cebranopadol retains its effect on cocaine consumption throughout a 7-day chronic treatment, suggesting a lack of tolerance development toward its effect. Finally, we found that only simultaneous blockade of NOP and MOP receptors by concomitant administration of the NOP antagonist SB-612111 (30 mg/kg) and naltrexone (2.5 mg/kg) reversed cebranopadol-induced decrease of cocaine SA, demonstrating that cebranopadol activates both NOP and classical opioid receptors to exert its effect. Our data, together with the fairly advanced clinical development of cebranopadol and its good tolerability profile in humans, indicate that cebranopadol is an appealing candidate for cocaine addiction treatment.

Cebranopadol, a Mixed Opioid Agonist, Reduces Cocaine Self-administration through Nociceptin Opioid and Mu Opioid Receptors

SHEN, QIANWEI;Ciccocioppo, Roberto;Cannella, Nazzareno
2017-01-01

Abstract

Cocaine addiction is a widespread psychiatric condition still waiting for approved efficacious medications. Previous studies suggested that simultaneous activation of nociceptin opioid (NOP) and mu opioid (MOP) receptors could be a successful strategy to treat cocaine addiction, but the paucity of molecules co-activating both receptors with comparable potency has hampered this line of research. Cebranopadol is a non-selective opioid agonist that at nanomolar concentration activates both NOP and MOP receptors and that recently reached phase-III clinical trials for cancer pain treatment. Here, we tested the effect of cebranopadol on cocaine self-administration (SA) in the rat. We found that under a fixed-ratio-5 schedule of reinforcement, cebranopadol (25 and 50 µg/kg) decreased cocaine but not saccharin SA, indicating a specific inhibition of psychostimulant consumption. In addition, cebranopadol (50 µg/kg) decreased the motivation for cocaine as detected by reduction of the break point measured in a progressive-ratio paradigm. Next, we found that cebranopadol retains its effect on cocaine consumption throughout a 7-day chronic treatment, suggesting a lack of tolerance development toward its effect. Finally, we found that only simultaneous blockade of NOP and MOP receptors by concomitant administration of the NOP antagonist SB-612111 (30 mg/kg) and naltrexone (2.5 mg/kg) reversed cebranopadol-induced decrease of cocaine SA, demonstrating that cebranopadol activates both NOP and classical opioid receptors to exert its effect. Our data, together with the fairly advanced clinical development of cebranopadol and its good tolerability profile in humans, indicate that cebranopadol is an appealing candidate for cocaine addiction treatment.
2017
262
File in questo prodotto:
File Dimensione Formato  
Frontiers in Psychiatry 2017 articolo234.pdf

accesso aperto

Descrizione: Copyright © 2017 Shen, Deng, Ciccocioppo and Cannella. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Tipologia: Versione Editoriale
Licenza: PUBBLICO - Creative Commons
Dimensione 591.44 kB
Formato Adobe PDF
591.44 kB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/405938
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 25
  • ???jsp.display-item.citation.isi??? 23
social impact