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Background: Morphine is widely used in clinical practice for a class of analgesic drugs, long-term use of morphine will cause the action of tolerance. MicroRNAs have been reported to be involved in morphine analgesic tolerance.. Methods: Forty male SD rats were selected and randomly divided into 5 groups: the control group, morphine tolerance group, miR-365 mimic + morphine (miR-365 mimic) group, miR-365 inhibitor + morphine (miR-365 inhibitor) group and miR-365 negative control (NC) + morphine (miR-365 NC) group. After the administration of morphine at 0 d, 1 d, 3 d, 5 d and 7 d, behavioral testing was performed. A dual luciferase reporter gene assay was performed to confirm the relationship between miR-365 and β-arrestin2, RT-qPCR was used to detect miR-365, β-arrestin2, ERK and CREB mRNA expressions, western blotting was used to evaluate the protein expressions of β-arrestin2, ERK, p-ERK, CREB and p-CREB, ELISA was used to detect the contents of IL-1β, TNF-α and IL-18, while immunofluorescence staining was used to measure the GFAP expression. Intrathecal injection of mir365 significantly increased the maximal possible analgesic effect (%MPE) in morphine tolerant rats. β-arrestin2 was the target gene of miR-365. Results: The results obtained showed that when compared with the morphine tolerance group, there was an increase in miR-365 expression and a decrease in the β-arrestin2, ERK, CREB protein expressions, contents of IL-1β, TNF-α, IL-18 and GFAP expression in the miR-365 mimic group, while the miR-365 inhibitor group displayed an opposite trend. Conclusions: The results of this experiment suggest that by targeting β-arrestin2 to reduce the contents of IL-1β, TNF-α and IL-18 and by inhibiting the activation of ERK/CREB signaling pathway, miR-365 could lower morphine analgesic tolerance. [ABSTRACT FROM AUTHOR]