Morphine CPP was unchanged in mice lacking the kappa opioid receptor (Simonin et al., 1998), as well as dynorphin (Mizoguchi et al., 2010; Zimmer et al., 2001). Prodynorphin KO mice showed unchanged (Mizoguchi et al., 2010; Zimmer et al., 2001) or increased hyperlocomotor activity upon morphine administration (Mizoguchi et al., 2010), suggesting that dynorphin opposes mu receptor signaling for the control of locomotor effects. Several signs of naloxone-induced withdrawal were decreased in morphine-dependent kappa KO mice (Simonin et al., 1998), an effect that could not be observed in pDyn mutants (Zimmer et al., 2001). A tonic role for the kappa/dynorphin system is therefore detected in dependent animals, at receptor level, in agreement with pharmacological studies suggesting protective role of kappa receptor blockade in morphine dependence (Wee and Koob, 2010). Involvement of this antireward system (Koob and Le Moal, 2008) is overall better detected in knockout mice under conditions of stress (Bruchas et al., 2010) and in response to non-opioid drugs of abuse (see below).
