β-endorphin KO animals compared with wild-type controls spent equal (Niikura et al., 2008) or more (Skoubis et al., 2005) time in the drug-paired compartment, depending on the dose and paradigm used. No modification of morphine CPP could be detected in proenkephalin (pEnk) KO mice (Skoubis et al., 2005), and physical dependence was either decreased (Shoblock and Maidment, 2007) or enhanced in these mice (Nitsche et al., 2002). These results suggest paradoxical negative modulatory roles for the two endogenous peptides in morphine reward (βend) and withdrawal (pEnk), or that compensatory mechanisms have developed in knockout animals.
