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Morphine tolerance (MT) caused by long-term use of morphine is a major medical problem. The underlying molecular mechanisms of morphine tolerance remain unclear. Here, we establish the morphine tolerance model in mice and verify whether a novel circRNA, circRalgapa1 is involved in morphine tolerance and its specific molecular mechanism. We show that the expression of circRalgapa1 in the spinal cord is significantly down-expressed in the spinal cord of morphine-tolerant mice. CircRalgapa1 is mainly located in the neuronal cytoplasm and co-localizes with miR-873a-5p. Mechanically, circRalgapa1 acts as competing endogenous RNAs (ceRNAs) to regulate the inhibitory of miR-873a-5p on A20 (also known as tumor necrosis factor α-induced protein 3, TNFAIP3). Functionally, overexpression of circRalgapa1 by intrathecal injection of adeno-associated virus (AAV- circRalgapa1) attenuated the formation of morphine tolerance and partially reversed the development of morphine tolerance. Moreover, overexpression of miR-873a-5p blocked the effect of AAV-circRalgapa1 on alleviating morphine tolerance in mice. In conclusion, chronic morphine administration-mediated down-regulation of circRalgapa1 in the spinal cord contributes to morphine tolerance via miR-873a-5p/A20 axis in mice. Overexpression of circRalgapa1 may be a promising RNA-based therapy for morphine tolerance. Schematic diagram for the proposed mechanisms of circRalgapa1 regulates morphine tolerance.Chronic application of morphine down-regulates circRalgapa1 in the spinal cord of mice, attenuating the competitive binding with miR-873a-5p, enhancing the inhibition of miR-873a-5p to A20 mRNA, thus reducing A20 expression to induce morphine tolerance in mice. [Display omitted] • CircRalgapa1 is down-regulated during induction of morphine tolerance. • CircRalgapa1 contributes to morphine tolerance via miR-873a-5p/A20 axis. • Overexpression of circRalgapa1 attenuates the formation and development of morphine tolerance. [ABSTRACT FROM AUTHOR]