Both pharmacological studies and genetic approaches provide considerable evidence suggesting that cannabinoid and opioid systems interact bi-directionally to regulate both neurochemical effects of drug and behavioral responses (Trigo et al., 2010; Vigano et al., 2005). Although mechanisms underlying functional interactions remain unclear, receptors from the two systems show overlapping distribution in various brain structures, and potential heterodimer formation between CB1 and mu opioid receptors has been suggested from in vitro studies (Maldonado et al., 2011; Solinas et al., 2008). Data summarizing cannabinoid effects in KO mice for the opioid system are shown in Table 2. THC-induced CPP was unchanged in delta or kappa KO mice (Ghozland et al., 2002), but was abolished in mu KO mutants (Ghozland et al., 2002) and the double mu-delta KO line (Castane et al., 2003), suggesting that mu receptors mediate rewarding properties of THC. Interestingly 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
