Pharmacological, molecular, and genetic data generated at both the preclinical and clinical levels implicate numerous stress-related neuropetidergic systems in the regulation of aspects of alcohol abuse. Among these, substantial evidence indicates involvement of the Nociceptin/Orphain FQ N/OFQ system: several publications have demonstrated that N/OFQ regulates ethanol preference, ethanol reward, and ethanol-seeking behavior (Ciccocioppo et al., 2004; Economidou et al., 2006; Kuzmin, et al., 2007). Specifically, activation of NOP receptors by N/OFQ has been shown to inhibit home cage ethanol drinking as well as operant ethanol self-administration (Ciccocioppo et al., 2004; Economidou et al., 2006). N/OFQ also reduces both ethanol-induced conditioned place preference and conditioned reinstatement of alcohol seeking (Ciccocioppo et al., 2004). Moreover, N/OFQ inhibits stress-induced ethanol-seeking and exerts general anti-stress effects by acting as a functional antagonist of extrahypothalamic corticotropin-releasing factor (CRH) transmission (Ciccocioppo et al., 2003; Martin-Fardon et al., 2000).
