Knockout studies have highlighted very distinct roles for each component of the opioid system in drug reward and dependence: the mu receptor is a convergent molecular target mediating rewarding properties of all drugs of abuse, the kappa receptor opposes mu receptor signaling in the control of hedonic homeostasis, and also mediates aversive effects of cannabinoids and nicotine, and the delta receptor most likely modulates drug consumption indirectly, by improving emotional states or facilitating drug-context association (see (Lutz and Kieffer, 2012, 2013). Confronting data from receptor KO and peptide KO mice is a difficult task, since ideally behavioral responses of the six knockout lines should be examined in parallel, using the same experimental setting. This was performed with the three receptor lines for some responses, but was never achieved for the six lines together. Also studies from constitutive gene deletions have sometimes yielded results which are discordant with behavioral pharmacology, often attributed to compensatory mechanisms that may develop in genetically modified animals (Kieffer and Gaveriaux-Ruff, 2002; Portugal and Gould, 2008). Altogether however, data analysis across the literature allows identification of potential
