The differential effects of OX1R and OX2R selective antagonists on morphine conditioned place preference in naïve versus morphine-dependent mice.

Conditioned place preference (CPP) has been associated with orexinergic (hypocrtinergic) system activation in naïve mice; however, the distinct role of different receptors of orexin in this paradigm has not been characterized yet. Moreover, the relationship between orexins and morphine in dependent mice may not be equal to naïve mice and seems noteworthy to investigate. We investigated the effects of systemic administration of orexin-1-receptor antagonist, SB 334867, and orexin-2 receptor antagonist, TCS-OX2-29 on the acquisition and expression of morphine conditioned place preference (CPP) in both naïve and morphine-dependent mice. We tested SB 334867 in three doses (10, 20 and 30 mg/kg), TCS-OX2-29 in two doses (5 and 10 mg/kg) and morphine with highest effective dose based on our dose-response experiment (5 mg/kg). Our results revealed that while SB 334867 suppressed CPP acquisition and expression in naïve mice, it failed to block CPP acquisition and expression in morphine dependent animals. In contrast, TCS-OX2-29 suppressed CPP acquisition and expression in both naïve and dependent mice significantly. The rewarding effect of morphine has stronger correlation with orexin-2 receptors in morphine-dependent mice while it depends on both kinds of receptors in naïve mice. This finding, if confirmed in other studies, persuades us to further investigate the role of orexin-2 receptor antagonists as potent drugs in addiction treatment.