withdrawal-related anxiety and drinking. For example, infusion of nociceptin into brain ventricles reduced alcohol conditioned reward as well as relapse-like behavior provoked by either stress or alcohol-related cues (Ciccocioppo et al., 2004; Martin-Fardon et al., 2000). Likewise, systemic administration of brain-penetrant nociception analogues reduced alcohol self-administration (Aziz et al., 2016; Ciccocioppo et al., 2014; Kuzmin et al., 2007). Direct injection of nociceptin into the CeA also was reported to reduce alcohol consumption (Economidou et al., 2008). This effect may be mediated by nociception interacting with alcohol-induced modulation of GABA and glutamate transmission in the CeA (Kallupi et al., 2014a; Kallupi et al., 2014b). Additionally, chronic alcohol exposure appears to enhance sensitivity to NOP activation, as nociceptin (or its analogues) were shown to be more effective as anxiolytics and reducing elevated drinking associated with dependence (Aujla et al., 2013; Aziz et al., 2016; de Guglielmo et al., 2015; Economidou et al., 2011; Martin-Fardon et al., 2010).
