Buprenorphine requires concomitant activation of NOP and MOP receptors to reduce cocaine consumption - PubMed (original) (raw)

. 2018 Mar;23(2):585-595.

doi: 10.1111/adb.12513. Epub 2017 Jun 21.

Affiliations

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

Marsida Kallupi et al. Addict Biol. 2018 Mar.

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.

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

© 2017 Society for the Study of Addiction.

PubMed Disclaimer

Conflict of interest statement

Disclosure/Conflict of Interest

The authors report no biomedical financial interests or potential conflicts of interest. M.K. conducted the experiments and wrote the manuscript. N.Z. provided the compounds AT-034, AT-201 and AT-202 and helped with the interpretation of the data. G.d.G. performed the experiments and analyzed the data. Q.S., D.Y. and V.B.J. helped with the experiments and data collection. R.C. designed, supervised the study and contributed to prepare and write the manuscript.

Figures

Figure 1

Figure 1

Effect of buprenorphine on cocaine and saccharin self-administration: at all doses tested, buprenorphine significantly and in a dose-dependent manner reduced (a) the number of cocaine rewards (b), whereas inactive lever response was not affected by treatment. (c) At the middle, effective dose of 1.0 mg/kg buprenorphine neither affected saccharin self-administration (d) nor modified inactive lever responses. Difference from controls (0.0): *P < 0.05 or **P < 0.01

Figure 2

Figure 2

Effect of naltrexone (Nltx) and of SB-612111 (SB) on cocaine self-administration: Nltx neither modified (a) cocaine self-administration (b) nor affected inactive control lever responding. Similarly, SB was unable to change cocaine-related operant responding at both (c) active and (d) inactive levers

Figure 3

Figure 3

Effect of naltrexone (Nltx) and of SB-612111 (SB) on buprenorphine-induced (1.0 mg/kg) reduction of cocaine self-administration: (a) Buprenorphine (1.0 mg/kg) significantly reduced cocaine self-administration. At all dose tested, Nltx (0.0, 0.25, 1.0 and 2.5 mg/kg) was unable to prevent this effect of buprenorphine. (b) Inactive lever responding was not modified by drug treatments. (c) Again, buprenorphine (1.0 mg/kg) significantly reduced cocaine self-administration. The effect was not modified by any of the SB doses (0.0, 10.0, and 30 mg/kg) employed. (d) Inactive lever responding was not modified by drug treatments. Difference from controls (0.0/0.0): ***P < 0.001

Figure 4

Figure 4

Effect of naltrexone 2.5 mg/kg (Nltx 2.5) and of SB-612111 30.0 mg/kg (SB 30) or their combination (Nltx + SB) on buprenorphine-induced reduction of cocaine self-administration. (a) Buprenorphine (1 mg/kg) significantly reduced cocaine self-administration compared with vehicle-treated group (control). The effect was not modified by pre-treatment with Nltx 2.5 or SB 30.0 alone. However, when Nltx 2.5 and SB 30.0 were combined, they completely reversed the inhibitory effect of buprenorphine. (b) Inactive lever response was not affected by drug treatments. Differences from vehicle-treated animals (control): ***P < 0.001. Difference between buprenorphine plus vehicles (0.0/0.0) and the group treated with naltrexone plus SB-612111 (Nltx + SB): ###P < 0.0001. Difference between naltrexone (Ntlx 2.5) or SB-612111 (SB 30) alone with naltrexone plus SB-612111 (Nltx + SB): ααα_P_ < 0.001

Figure 5

Figure 5

Effect of AT-034 (0.0, 1.0, 3.0 or 10.0 mg/kg), AT-201 (0.0, 1.0, 3.0 or 10.0 mg/kg) or AT-202 (0.0, 1.0, 3.0 or 10.0 mg/kg) on cocaine self-administration: AT-034 significantly reduced (a) cocaine self-administration; (b) inactive lever responses was not affected by treatment. (c) Similarly, AT-0201 significantly reduced cocaine self-administration, while (d) inactive lever responses were not changed. AT-202 instead was ineffective and neither reduced (e) cocaine self-administration (f) nor inactive lever responding. Difference from controls (0.0): *P < 0.05

Figure 6

Figure 6

Effect of AT-034 (0.0, 1.0, 3.0 or 10.0 mg/kg), AT-201 (0.0, 1.0, 3.0 or 10.0 mg/kg) or AT-202 (0.0, 1.0, 3.0 or 10.0 mg/kg) on saccharin self-administration: AT-034 significantly reduced (a) saccharin self-administration; (b) inactive lever responses were not affected by treatment. (c) Similarly, AT-0201 significantly reduced saccharin self-administration; (d) inactive lever responses were not changed. AT-202 instead neither modified (e) saccharin self-administration (f) nor inactive lever responding. Difference from controls (0.0): ***P < 0.001

References

    1. Bebawy D, Marquez P, Samboul S, Parikh D, Hamid A, Lutfy K. Orphanin FQ/nociceptin not only blocks but also reverses behavioral adaptive changes induced by repeated cocaine in mice. Biol Psychiatry. 2010;68:223–230. -PMC -PubMed
    1. Bidlack JM. Mixed kappa/mu partial opioid agonists as potential treatments for cocaine dependence. Adv Pharmacol. 2014;69:387–418. -PubMed
    1. Bloms-Funke P, Gillen C, Schuettler AJ, Wnendt S. Agonistic effects of the opioid buprenorphine on the nociceptin/OFQ receptor. Peptides. 2000;21:1141–1146. -PubMed
    1. Ciccocioppo R, Economidou D, Rimondini R, Sommer W, Massi M, Heilig M. Buprenorphine reduces alcohol drinking through activation of the nociceptin/orphanin FQ-NOP receptor system. Biol Psychiatry. 2007;61:4–12. -PMC -PubMed
    1. Cippitelli A, Schoch J, Debevec G, Brunori G, Zaveri NT, Toll L. A key role for the N/OFQ-NOP receptor system in modulating nicotine taking in a model of nicotine and alcohol co-administration. Sci Rep. 2016;6:26594. -PMC -PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources