, 1995). N/OFQ and its receptor, NOPR, are widely expressed in the brain, where they control the release of other neurotransmitters through presynaptic actions (Darland et al., 1998; Neal et al.,
1999). Despite its structural homology with opioid peptides, N/OFQ does not bind to the opioid receptors and, conversely, opioid peptides do not activate the NOPR (Reinscheid et al., 1996). Additionally, while opioid-like N/OFQ elicits pronociceptive effects after intracranial administration, giving rise to the name nociceptin (Meunier et al., 1995), and acts in the brain to produce functional antiopioid effects, it blocks opioid-induced supraspinal analgesia (Mogil et al., 1996), morphine-induced CPP (Ciccocioppo et al., 2000; Murphy et al., 1999), and this website morphine-induced increases in extracellular DA levels in the nucleus accumbens (NAC) (Di Giannuario and Akt inhibitor Pieretti, 2000). 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 CeA, an effect that is more pronounced in slice preparations from rats undergoing alcohol withdrawal, a state known to be associated with Mephenoxalone 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 antistress and anxiolytic-like effects when the CRF system is activated. This view is supported by gene expression data showing that exposure to stressful conditions, such as alcohol withdrawal or intracranial CRF administration, leads to upregulated NOPR expression in the BNST, which may explain in part the enhanced efficacy of N/OFQ to produce antistress effects under these conditions (Martin-Fardon et al., 2010; Rodi et al., 2008). Several studies have demonstrated that activation of the NOPR blunts the reinforcing and motivational effects of alcohol across a range of behavioral measures, including alcohol intake (Ciccocioppo et al., 1999), CPP (Kuzmin et al., 2003), and relapse to alcohol seeking triggered by alcohol-associated cues (Ciccocioppo et al., 2004) or stress (Martin-Fardon et al., 2000). The latter result is particularly noteworthy, because relapse-like behavior triggered by stress or cues are otherwise to a large degree pharmacologically dissociable (Shalev et al., 2002).