Background and Objective: Morphine tolerance is induced by repeated exposure to the opioid. The prefrontal cortex (PFC) is a target of the mesocorticolimbic pathway, which is involved in the action of morphine on the brain. Molecular studies have shown that during morphine tolerance, the expression of the mu-opioid receptors is affected, which may partly underlie in the induction of morphine tolerance. Some recent researches have proposed some roles for microRNAs in controlling gene expression, and it has been shown that among many studied miRNAs, the Mir124, Mir219 and Mir339 are involved in the regulation of the morphine tolerance in some areas of the brain. The aim of this study was to examine changes in mu-opioid receptors and its association with Mir124, Mir219 and Mir339 in the PFC after induction of morphine tolerance in rats. Method: Male Wistar rats were used in which morphine tolerance was induced with eight days injections of morphine 10 mg/kg (i.p.) twice per day. Two groups of rats received saline (1 ml/kg) or morphine (10 mg/kg) twice daily for 8 days. On day 8, morphine-induced analgesic tolerance was assessed using a hotplate test of analgesia. For gene expression study, the PFC was extracted in the separate saline or morphine-treated groups on day 8 of the schedule to examine changes in gene expression of the mu-opioid or the miRNAs using a quantitative RT-PCR method. Result: The results showed that morphine treatment for 8 days induced analgesic tolerance. The results of the qRT-PCR showed that the mu-opioid receptor gene expression was significantly decreased (P<0.05) but no significant change was observed for Mir124, Mir219 and Mir339 expression in the PFC of the morphine-tolerant group compared to the saline-treated group. Conclusions: It can be concluded that changes in the gene expression of mu-opioid receptor in the PFC after repeated injections of morphine may underlie induction of morphine analgesic tolerance. However, Mir124, Mir219 and Mi
