Differential effects of intra-accumbal orexin-1 and -2 receptor antagonists on the expression and extinction of morphine-induced conditioned place preference in rats

• Intra-NAc OX1 receptor antagonist dose-dependently attenuated expression of morphine CPP.
• Intra-accumbal SB334867 shortened extinction period of morphine CPP in a dose-dependent manner.
• Blockade of OX2 receptors in the NAc could not decrease expression of morphine CPP.
• Intra-NAc OX2 receptor antagonist shortened the extinction period of morphine CPP.

Orexinergic neurons originate from the hypothalamic nuclei, sending projections toward mesolimbic regions such as the nucleus accumbens (NAc). In this study, an attempt was made to determine the effects of intra-accumbal administration of SB334867 as an orexin-1 receptor (OX1R) antagonist and TCS OX2 29 as an orexin-2 receptor (OX2R) antagonist in the expression and maintenance of morphine-induced conditioned place preference (CPP) in rats. One hundred and five adult Wistar rats weighing 200–280 g were bilaterally implanted with cannulae into the NAc. During the 3-day conditioning phase, animals received daily subcutaneous administration of morphine (5 mg/kg). CPP score and locomotor activity of animals were recorded by Ethovision software. Different doses of bilateral injections of the OX1R and OX2R antagonists (3, 30 and 300 μg/0.5 μl DMSO) were administered just before the conditioning test or daily injection during extinction phase. Our finding revealed that intra-accumbal administration of OX1R not OX2R antagonist just before the CPP test attenuated the expression of the morphine-induced CPP. However, the blockade of these two kinds of receptors shortened the extinction phase in the rats. This effect was more significant in intra-NAc OX1R antagonist-treated animals. The results suggested that OX1R within the NAc may be necessary for the morphine-induced expression. Additionally, it seems that the existence of the orexin receptors in the NAc was important for the maintenance of morphine rewarding properties during the extinction phase. Therefore, orexins may be considered as a promising therapeutic agent in preventing the expression and maintenance of morphine rewarding effects on dependent individuals.