concur to indicate that morphine reward and motivation to obtain the drug are intact in these animals, however drug-context association is impaired. A subsequent study showed that internal or external non-spatial cues (circadian, drug, auditory) predicting drug or food reward restored morphine CPP in delta KO mice, suggesting that only contextual learning is impaired in these mice (Le Merrer et al., 2012). Considering locomotor effects, the stimulant effect of acute morphine was unchanged in delta KO mice (Chefer et al., 2003). However, sensitization or tolerance to this effect, observed upon distinct regimen of chronic morphine administration, were enhanced and reduced respectively (Chefer and Shippenberg, 2009), indicating a role for delta receptors in these adaptive responses to chronic morphine. Otherwise, physical dependence was unchanged in delta KO mice (Nitsche et al., 2002). In conclusion, the delta receptor does not directly mediate morphine reward and likely facilitates contextual learning. Also, as many other systems, this receptor contributes to chronic morphine-induced neuroplasticity. Mechanisms underlying a potential cross talk between delta receptor activity and mu opioid receptor signaling in vivo remain unclear (see (Pradhan et al., 2011; Stockton and Devi, 2012).
