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.

NOP-Related Mechanisms in Substance Use Disorders

“…Interestingly, this effect was evident only at highest doses of buprenorphine and appeared to be independent from reductions in heroin use. This clinical study replicated evidence from a number of preclinical investigations that systematically demonstrated the efficacy of buprenorphine in attenuating cocaine selfadministration in rats and monkeys and humans (Lukas et al, 1995;Montoya et al, 2004;Sorge et al, 2005;Sorge & Stewart, 2006;Kallupi et al, 2018). In some circumstances, the "therapeutic" effect of buprenorphine on cocaine intake was attenuated by administration of naltrexone (Mello et al, 1993;Wee et al, 2012).…”

“…Growing evidence suggests that compounds that co-activate MOP and NOP opioid receptors (Table 4) have potential for the treatment of drug abuse (Ciccocioppo et al, 2007;Toll et al, 2009;Kallupi et al, 2018).…”

Effects of stimulation of mu opioid and nociceptin/orphanin FQ peptide (NOP) receptors on alcohol drinking in rhesus monkeys

“…Future studies will be necessary to characterize the relative contribution of MOP and NOP receptors to the therapeutic effects of bifunctional MOP/NOP agonists such as BU08028. A role for both receptor systems in the ability of buprenorphine to decrease alcohol self-administration would be consistent with its effects on cocaine self-administration [79]. In the present studies, the acute effects of SCH 221510, a NOP receptor agonist with 217-fold selectivity in binding and 58-fold selectivity in stimulating NOP vs. MOP receptors [11], were similar to those of buprenorphine and BU08028.…”

Cebranopadol Blocks the Escalation of Cocaine Intake and Conditioned Reinstatement of Cocaine Seeking in Rats

“…Accumulating evidence indicates that a novel strategy that targets both nociceptin/orphanin FQ peptide (NOP) receptors and m-opioid receptors (MORs) may be useful for the treatment of addictions (Khroyan et al, 2007(Khroyan et al, ,2011Toll, 2013;Kallupi et al, 2017a). Buprenorphine is a MOR and NOP receptor partial agonist that has been approved for the treatment of opioid use disorder and has been shown to attenuate the expression of cocaine sensitization in rats (Placenza et al, 2008).…”

“…For example, NOP receptor agonists have been reported to increase the analgesic effects of MOR agonists (Courteix et al, 2004;Cremeans et al, 2012), decrease dopamine release from neurons in brain areas that are associated with the reward pathway (Ikemoto and Panksepp, 1999;Toll, 2013), decrease morphine-induced conditioned place preference (Ciccocioppo et al, 2000), and attenuate the rewarding effects of opioids in rats (Murphy et al, 1999;Rutten et al, 2010). Interestingly, recent results showed that buprenorphine requires concomitant activation of NOP and MOP receptors to reduce cocaine consumption in rats (Kallupi et al, 2017a). This evidence suggests that compounds with high efficacy at MORs and NOP receptors may be useful for the treatment of drug addiction.…”