A key role for the N/OFQ-NOP receptor system in modulating nicotine taking in a model of nicotine and alcohol co-administration

Cippitelli, Andrea; Schoch, Jennifer J.; Debevec, Ginamarie; Brunori, Gloria; Zaveri, Nurulain T.; Toll, Lawrence

doi:10.1038/srep26594

Cited by 29 publications

(26 citation statements)

References 60 publications

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“…The NOP full agonist AT‐202 given at pharmacologically effective doses (Toll et al ) did not show effects on cocaine and saccharin intake. Notably, in a previous study, it was found that AT‐202 dose dependently increased nicotine taking in nicotine‐dependent and non‐dependent rats, while it did not affect alcohol intake in a co‐administration paradigm (Cippitelli et al ). Here, neither cocaine nor saccharin consumption was modified by AT‐202, suggesting that intake facilitation was specific for nicotine.…”

Section: Discussionmentioning

confidence: 90%

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

et al. 2017

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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.

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Section: Discussionmentioning

confidence: 90%

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

et al. 2017

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“…After the acute withdrawal phase, stressors, a small amount of nicotine (i.e., lapse), and cues contribute to relapse. The reviewed studies indicate that blockade of hypocretin-1 and nociception receptors, and stimulation of galanin, neurotensin, and ghrelin receptors diminishes the rewarding effects of nicotine (Boules et al 2011; Cippitelli et al 2016; Hollander et al 2008; Jackson et al 2011; Jerlhag and Engel 2011). Overall, a different group of neuropeptides plays a role in nicotine withdrawal.…”

Section: Discussionmentioning

confidence: 99%

“…Several other neuropeptides have been implicated in the rewarding effects of nicotine including nociceptin/orphanin FQ, neurotensin, galanin, and ghrelin (Boules et al 2011; Cippitelli et al 2016; Jerlhag and Engel 2011). Nociceptin mediates its effects in the brain by acting upon the nociceptin receptor.…”

Section: Neuropeptides and The Rewarding Effects Of Nicotinementioning

confidence: 99%

“…Nociceptin mediates its effects in the brain by acting upon the nociceptin receptor. Stimulation of the nociceptin receptor with AT-202 increases nicotine self-administration and blockade of this receptor with SB612111 decreases nicotine self-administration in rats (Cippitelli et al 2016). Similar effects were observed in dependent and non-dependent rats.…”

Section: Neuropeptides and The Rewarding Effects Of Nicotinementioning

confidence: 99%

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Neuropeptide systems and new treatments for nicotine addiction

Bruijnzeel

2016

Psychopharmacology

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RATIONALE The mildly euphoric and cognitive enhancing effects of nicotine play a role in the initiation of smoking, while dysphoria and anxiety associated with smoking cessation contribute to relapse. After the acute withdrawal phase, smoking cues, a few cigarettes (i.e., lapse), and stressors can cause relapse. Human and animal studies have shown that neuropeptides play a critical role in nicotine addiction. OBJECTIVES The goal of this paper is to describe the role of neuropeptide systems in the initiation of nicotine intake, nicotine withdrawal, and the reinstatement of extinguished nicotine seeking. RESULTS The reviewed studies indicate that several drugs that target neuropeptide systems diminish the rewarding effects of nicotine by preventing the activation of dopaminergic systems. Other peptide-based drugs diminish the hyperactivity of brain stress systems and diminish withdrawal-associated symptom severity. Blockade of hypocretin-1 and nociceptin receptors and stimulation of galanin and neurotensin receptors diminishes the rewarding effects of nicotine. Both corticotropin-releasing factor type 1 and kappa-opioid receptor antagonists diminish dysphoria and anxiety-like behavior associated with nicotine withdrawal and inhibit stress-induced reinstatement of nicotine seeking. Furthermore, blockade of vasopressin 1b receptors diminishes dysphoria during nicotine withdrawal and melanocortin 4 receptor blockade prevents stress-induced reinstatement of nicotine seeking. The role of neuropeptide systems in nicotine-primed and cue-induced reinstatement is largely unexplored, but there is evidence for a role of hypocretin-1 receptors in cue-induced reinstatement of nicotine seeking. CONCLUSION Drugs that target neuropeptide systems might decrease the euphoric effects of smoking and improve relapse rates by diminishing withdrawal symptoms and improving stress resilience.

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“…Intracerebroventricular nociceptin administration inhibited cocaine-induced CPP (Kotlinska et al, 2002). In contrast to these reports, recent data showed that genetic deletion of the nociceptin receptor in rats conferred resilience to abused psychoactive drugs (Kallupi et al, 2017), and NOP antagonism blocked both nicotine and alcohol self-administration in a co-administration paradigm (Cippitelli et al, 2016). One hypothesis is that these effects of NOP agonists are mediated by mechanisms that involve the downregulation or desensitization of NOP receptors (Ciccocioppo et al, 2014).…”

Section: Discussionmentioning

confidence: 90%

Cebranopadol blocks the escalation of cocaine intake and conditioned reinstatement of cocaine seeking in rats

Guglielmo

Matzeu

Kononoff

et al. 2017

Preprint

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Cebranopadol is a novel agonist of nociceptin/orphanin FQ peptide (NOP) and opioid receptors with analgesic properties that is being evaluated in clinical Phase 2 and Phase 3 trials for the treatment of chronic and acute pain. Recent evidence indicates that the combination of opioid and NOP receptor agonism may be a new treatment strategy for cocaine addiction. We sought to extend these findings by examining the effects of cebranopadol on cocaine self-administration (0.5 mg/kg/infusion) and cocaine conditioned reinstatement in rats with extended access to cocaine. Oral administration of cebranopadol (0, 25, and 50 µg/kg) reversed the escalation of cocaine self-administration in rats that were given extended (6 h) access to cocaine, whereas it did not affect the self-administration of sweetened condensed milk (SCM). Cebranopadol induced conditioned place preference but did not affect locomotor activity during the conditioning sessions. Finally, cebranopadol blocked the conditioned reinstatement of cocaine seeking. These results show that oral cebranopadol treatment prevented addiction-like behaviors (i.e., the escalation of intake and reinstatement), suggesting that it may be a novel strategy for the treatment of cocaine use disorder. However, the conditioned place preference that was observed after cebranopadol administration suggests that this compound may have some intrinsic rewarding effects.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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A key role for the N/OFQ-NOP receptor system in modulating nicotine taking in a model of nicotine and alcohol co-administration

Cited by 29 publications

References 60 publications

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

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

Neuropeptide systems and new treatments for nicotine addiction

Cebranopadol blocks the escalation of cocaine intake and conditioned reinstatement of cocaine seeking in rats

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