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), conditioned place preference (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). Neurocircuitry mediating aversive emotional states is implied in stress-induced relapse by the ability of CRF1R antagonists to block this behavior. In contrast, appetitive mechanisms are implied in cue-induced relapse to alcohol seeking, since it is blocked by the mu opioid receptor-preferring antagonist naltrexone, which also blocks ongoing alcohol self-administration in non-dependent rats (Le et al., 2000; Le et al., 1999; Liu and Weiss, 2002). The ability of N/OFQ to block both stress- and cue-induced relapse therefore raises two distinct possibilities. One is that N/OFQ simply acts at multiple sites in the brain to modulate both aversive and
