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While for heroin it has been demonstrated that the effect of buprenorphine is mediated by its ability to activate \u03bc\u2010opioid 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\u2010administer cocaine for 2\u00a0hours daily. Buprenorphine (0.3, 1.0 and 3.0\u00a0mg\/kg) given intraperitoneally 90\u00a0minutes before access to cocaine significantly and dose dependently reduced its intake. Pre\u2010treatment with naltrexone or with the selective nociceptin\/orphanin FQ peptide (NOP) antagonist SB\u2010612111 did not prevent buprenorphine\u2010induced reduction of cocaine intake. However, when naltrexone and SB\u2010612111 were combined, the effect of buprenorphine on cocaine was completely prevented. To confirm that co\u2010activation of MOP and NOP receptors is the underlying mechanism through which buprenorphine reduces cocaine intake, three compounds, namely, AT\u2010034, AT\u2010201 and AT\u2010202, with a range of affinity and intrinsic activity profiles for MOP and NOP receptors, but weak ability for kappa\u2010opioid peptide receptor (KOP) transmission, were tested. Consistent with our hypothesis based on buprenorphine's effects, results demonstrated that AT\u2010034 and AT\u2010201, which co\u2010activate MOP and NOP receptors, reduced cocaine self\u2010administration like buprenorphine. AT\u2010202, which selectively stimulates NOP receptors, was not effective. Together, these data demonstrate that for buprenorphine, co\u2010activation 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.<\/jats:p>","DOI":"10.1111\/adb.12513","type":"journal-article","created":{"date-parts":[[2017,6,21]],"date-time":"2017-06-21T06:16:36Z","timestamp":1498025796000},"page":"585-595","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Buprenorphine requires concomitant activation of NOP and MOP receptors to reduce cocaine consumption"],"prefix":"10.1111","volume":"23","author":[{"given":"Marsida","family":"Kallupi","sequence":"first","affiliation":[{"name":"School of Pharmacy, Pharmacology Unit University of Camerino Italy"},{"name":"Committee on the Neurobiology of Addictive Disorders The Scripps Research Institute La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianwei","family":"Shen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Pharmacology Unit University of Camerino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giordano","family":"de Guglielmo","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Pharmacology Unit University of Camerino Italy"},{"name":"Committee on the Neurobiology of Addictive Disorders The Scripps Research Institute La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Yasuda","sequence":"additional","affiliation":[{"name":"Astraea Therapeutics Mountain View CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V. 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