Activation of NOPR produces anxiolytic-like effects (Gavioli and Calo, 2006; Varty et al., 2005) that appear to be particularly robust under stressful conditions, such as during alcohol withdrawal (Economidou et al., 2011). This may depend upon the ability of N/OFQ to act as a functional antagonist for extrahypothalamic actions of CRF and CRF1R activation. For instance, it has been shown that N/OFQ blocks the anorectic and the anxiogenic-like effects of CRF, with the BNST being the site of the interaction between the two systems (Ciccocioppo et al., 2003; Rodi et al., 2008). In addition, N/OFQ opposes the ability of CRF to facilitate GABAergic transmission in the central amygdala, an effect that is more pronounced in slice preparations from rats undergoing alcohol withdrawal, a state known to be associated with enhanced stress reactivity and overactive CRF neurotransmission (Cruz et al., 2012). These data provide converging evidence supporting the possibility that NOPR activation may result in particularly beneficial anti-stress and anxiolytic-like effects when the CRF system is activated. This view is supported by gene expression data showing that exposure to stressful conditions,
