conditioned place aversion (CPA), typically observed at a high dose of THC in wild-type mice, was abolished in both pDyn (Zimmer et al., 2001) and kappa KO mice (Ghozland et al., 2002). The latter observations indicate that the kappa/dynorphin system mediates aversive effects of THC, another facet of cannabinoid effects. This was further supported by facilitated self-administration of WIN, a cannabinoid agonist, in pDyn KO mice (Mendizabal et al., 2006). It has long been established that mu and kappa receptors oppositely regulate hedonic homeostasis (Spanagel et al., 1992) and it is therefore possible that the same opposing activities of the two opioid receptors mediate the well-know dual euphoric/aversive effects of cannabinoids. Notably, the delta receptor does not seem involved in all these THC effects, at least from knockout mice analysis (Ghozland et al., 2002).
