Conflicting accounts of the selectivity and time-dependent nature of KOR antagonist effects have also been reported. Two commonly used antagonists, nor-BNI and JDtic, both have a slow onset of action, with peak efficacy and selectivity often observed 24 hr after systemic administration (Carroll et al., 2004; Endoh et al., 1992; Broadbear et al., 1994). However, two studies that reported behavioral effects of nor-BNI or JDTic 2 hr but not 24 hr after administration contradict this assertion (Schank et al., 2012a; Funk et al., 2014). Further complicating interpretation of the pharmacological properties of nor-BNI, some older studies have reported mu opioid receptor antagonist properties up to 2 hours after administration (e.g., Endoh et al., 1992; Broadbear et al. 1994). Another report demonstrated dose- and time-dependent mu antagonist activity of nor-BNI, suggesting that higher doses of the KOR antagonist extend the time course of mu antagonist effects (Wettstein and Grouhel, 1996). Finally, a more recent report calls into question the selectivity of nor-BNI by demonstrating efficacy of the drug in mice lacking KOR receptors (Zhou et al., 2015). These characteristics suggest that,
