miR-219-5p targets CaMKIIγ to attenuate morphine tolerance in rats

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.

The Regulatory Mechanisms and Therapeutic Potential of MicroRNAs: From Chronic Pain to Morphine Tolerance

“…Thus, miR-219 is associated with the development of morphine tolerance in mouse dorsal root. Another study demonstrated that miR-219-5p attenuated morphine tolerance by targeting CaMKIIγ in rats (Jian et al, 2017 ).…”

Identification of lncRNA expression profiles and ceRNA analysis in the spinal cord of morphine-tolerant rats

“…In our previous study, We have confirmed that miR-219-5p can attenuate morphine tolerance by targeting CaMKIIγ [ 12 ]. Furthermore, other researchers have also reported that miR-219 is down-regulated following the continuous application of morphine and can regulate NMDA receptor signaling [ 36 ].…”

“…Next, we considered several criteria to select lncRNAs and mRNAs from our microarray data for validation. Firstly, we attempted to select the relevant candidates that might be related to our previous studies of morphine tolerance and miRNAs [ 11 , 12 ]. Secondly, for validation, we chose the lncRNA candidates that exhibited higher fold changes and greater raw expression intensities and had adjacent mRNA that was related to morphine tolerance.…”

“…The recent focus of this area is the role of non-coding RNAs (ncRNAs) [ 5 , 6 ]. Among ncRNAs, some studies have reported that miRNAs are involved in the development of morphine tolerance [ 7 , 8 ], including the let-7 family, miR-23b [ 9 ], miR-133b, miR-339 [ 10 ], miR-365 [ 11 ] and miR-219-5p [ 12 ]. However, the research regarding long non-coding RNAs (lncRNAs) is still in its infancy.…”

MicroRNA‐219a‐5p−mediated inhibition of CaMKIIγ facilitates vestibular compensation in acute vertigo by promoting protein kinase C expression

“…10 CaMKIIγ was reported to be expressed in the vasculature; 11 functional relationships among miRNAs and the CaMK family have been described previously; 12 and CaMKIIγ was identified as a target of miR-219a-5p. 13 Protein kinase C (PKC), initially discovered by Nishizuka and colleagues in 1977, was found to be activated in the presence of a low concentration of Ca 2+ . 14 Both CaMKII and PKC possess similar phosphoprotein profiles and total protein levels.…”