Abstract
Morphine tolerance is a clinical challenge in pain management. Emerging evidence suggests that microRNA (miRNA) plays a regulatory role in the development of morphine tolerance. miR-219-5p (miR-219) targets calmodulin-dependent protein kinase II γ (CaMKIIγ) to activate central pain sensitization via N-methyl-D-aspartate (NMDA) receptor. Therefore, we hypothesized that miR-219-5p attenuates morphine tolerance by targeting CaMKIIγ. We found that the expression of miR-219-5p was decreased significantly after chronic morphine treatment. Overexpression of miR-219-5p by lentivirus injection prevents the development of morphine tolerance. CaMKIIγ, the target gene of miR-219-5p was downregulated by overexpression of miR-219-5p both in vivo and in vitro. Furthermore, we found that lentiviral-mediated miR-219-5p decreased the expression of NMDA receptor subunit 1 (NR1), leading to attenuation of morphine tolerance. Overall, the data demonstrate that miR-219-5p plays a crucial role in alleviating morphine tolerance by inhibiting the CaMKII/NMDA receptor pathway. Overexpression of miR-219-5p may be a potential strategy to ameliorate morphine tolerance.
Highlights
Morphine is commonly used to alleviate moderateto-severe pain, especially cancer pain
We investigated the dynamic changes in miR-219-5p and calmodulin-dependent protein kinase II γ (CaMKIIγ) using the morphine tolerance model
We found that consecutive intrathecal administration of morphine decreased the expression of miR-219-5p in the spinal cord, and increased the expression of CaMKIIγ
Summary
Morphine is commonly used to alleviate moderateto-severe pain, especially cancer pain. Recent evidence suggests that post-translational regulation by miRNAs may mediate the development of morphine tolerance [2,3,4]. MicroRNAs (miRNAs) are small non-coding RNAs containing 18~22 nucleotides, which regulate gene expression at the translational level [5]. MiRNAs repress mRNA expression or destabilize mRNA by binding to the 3ʹ-untranslated region (UTR) of the target genes [6]. Thousands of miRNAs have been identified in humans, and are involved in the pathophysiology of various diseases[7]. Evidence indicates that miRNA is expressed abundantly in nervous system and serves as an important epigenetic regulator of neurobiological activity, including neurogenesis, neuronal plasticity and pain perception [8,9,10,11]. Morphine tolerance is of growing interest in the study of miRNA-mediated cellular adaptation
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