Contrary to these findings, recent reports suggest that blocking, rather than activating, NOP receptors may be effective in reducing alcohol self-administration. Genetic deletion of the nociception receptor in rats resulted in lower alcohol consumption compared to wildtype controls, while saccharin intake was unaltered (Kallupi et al., 2017). Further, systemic administration of NOP antagonists reduced alcohol self-administration in wildtype rats but was without effect in NOP-deficient rats (Kallupi et al., 2017). These results align with another report showing that oral administration of a NOP antagonist reduced alcohol consumption, motivation to work for alcohol, and stress (yohimbine)-induced reinstatement of alcohol-seeking behavior in rats (Rorick-Kehn et al., 2016). These effects produced by the nociceptin receptor antagonist were attributed to the drug blocking alcohol-induced dopamine release in the nucleus accumbens. Several explanations have been postulated to address these apparent contradictory results (NOP agonists and antagonists reduce alcohol consumption), including receptor translocation, ligand-biased receptor signaling, and brain regional differences in receptor variants (Rorick-Kehn et al., 2016). Future studies will need to resolve this issue as well as address the therapeutic potential of this target for treating alcohol use disorders and stress-related drinking in particular.
