NOP-Related Mechanisms in Substance Use Disorders

Abstract

Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide that was deorphanized in 1995 and has been widely studied since. The role of the N/OFQ system in drug abuse has attracted researchers' attention since its initial discovery. The first two scientific papers describing the effect of intracranial injection of N/OFQ appeared twenty years ago and reported efficacy of the peptide in attenuating alcohol intake whereas heroin self-admnistration was insensitive. Since then more than 100 scientific articles investigating the role of the N/OFQ and N/OFQ receptor (NOP) system in drug abuse have been published. The present article provides an historical overview of the advances in the field with focus on three major elements. First, the most robust data supportive of the efficacy of NOP agonists in treating drug abuse come from studies in the field of alcohol research, followed by psychostimulant and opioid research. In contrast, activation of NOP appears to facilitate nicotine consumption. Second, emerging data challenge the assumption that activation of NOP is the most appropriate strategy to attenuate consumption of substances of abuse. This assumption is based first on the observation that animals carrying an overexpression of NOP system components are more prone to consume substances of abuse, whereas NOP knockout rats are less motivated to self-administer heroin, alcohol and cocaine. Third, administration of NOP antagonists also reduces alcohol consumption. In addition, NOP blockade reduces nicotine selfadmnistration. Hypothetical mechanisms explaining this apparent paradox are discussed. Finally, we focus on the possibility that co-activation of NOP and mu opioid (MOP) receptors is an alternative strategy, readily testable in the clinic, to reduce the consumption of psychostimulants, opiates and, possibly, alcohol.

Detailed In Vitro Pharmacological Characterization of the Clinically Viable Nociceptin/Orphanin FQ Peptide Receptor Antagonist BTRX-246040

“…In addition, the tolerability and safety of BTRX-246040 once-daily dosing of 40 mg up to 8 weeks have been already demonstrated in clinical studies (Witkin et al, 2019). Collectively these features candidate BTRX-246040 as an essential pharmacological tool to further investigate the therapeutic potential of NOP antagonists as innovative drugs to treat depression (Gavioli and Calo, 2013), Parkinson's disease (Mercatelli et al, 2019), and possibly drug abuse 14 (Ciccocioppo et al, 2019) as well as to identify novel conditions/diseases where the blockade of the NOP receptor is associated with beneficial effects, including traumatic injuries of the central nervous system (Awwad et al, 2018;Sekine et al, 2018), post-traumatic stress disorders (Zhang et al, 2015;Genovese and Dobre, 2017), and sepsis (Carvalho et al, 2008;Williams et al, 2008). This article has not been copyedited and formatted.…”

“…Moreover, recent findings suggest that treatment of drug abuse might be an additional indication for NOP antagonists (Rorick-Kehn et al, 2016;Kallupi et al, 2017) (see for a detailed discussion of this topic (Ciccocioppo et al, 2019)).…”

The Role of the Central Amygdala in Alcohol Dependence

“…Subsequent studies reported similar effects using NOP antagonists Ciccocioppo et al 2019). For instance, the NOP antagonist LY2940094 decreased voluntary ethanol intake in alcohol-preferring and -nonpreferring rats .…”

“…There is an ongoing debate on the mechanisms underlying similar effects using both NOP agonists and antagonists in decreasing the motivation for alcohol. One possible explanation is that NOP agonists may act through mechanisms involving desensitization of the system (Ciccocioppo et al 2019).…”

Crosstalk between Opioid and Anti-Opioid Systems: An Overview and Its Possible Therapeutic Significance

“…The putative therapeutic potential of NOP antagonists comes from studies in genetically modified NOP knockout rats. These animals self-administered significantly smaller amounts of alcohol, cocaine, and heroin, but showed unimpaired motivation for saccharin, which is a natural reward [ 238 ]. Hence, this group of compounds is more effective in preventing drug abuse [ 239 ] than NOP agonists and has promising utility for treating drug addiction.…”