Morphine and microRNA Activity: Is There a Relation with Addiction?

Abstract

When we talk about drug addiction, we are really dealing with an extremely complex system in which there still remain many unknowns and where many empty spaces or missing links are still present. Recent studies have identified changes in the expression profiles of several specific miRNAs which affect the interactions between these molecules and their targets in various illnesses, including addiction, and which may serve as valuable targets for more efficient therapies. In this review, we summarize results which clearly demonstrate that several morphine-related miRNAs have roles in the mechanisms that define addiction. In this regard, morphine has been shown to have an important role in the regulation of different miRNAs, such as miR-let-7 [which works as a mediator of the movement of the mu opioid receptor (MOR) mRNA into P-bodies, leading to translational repression], miR-23b (involved in linking MOR expression and morphine treatment at the post-transcriptional level), and miR-190 (a key post-transcriptional repressor of neurogenic differentiation, NeuroD). Fentanyl increases NeuroD levels by reducing the amount of miR-190, but morphine does not affect the levels of NeuroD. We also discuss the relationship between morphine, miRNAs, and the immune system, based on the discovery that morphine treatment of monocytes led to a decrease in several anti-HIV miRNAs (mir-28, 125b, 150, and 382). This review is centered on miR-133b and its possible involvement in addiction through the effects of morphine. We establish the importance of miR-133b as a regulatory factor by summarizing its activity in different pathological processes, especially cancer. Using the zebrafish as a research model, we discuss the relationship between mir-133b, the dopaminergic system, and morphine, considering: (1) that morphine modulates the expression of miR-133b and of its target transcript Pitx3, (2) the role of the zebrafish mu opioid receptor (zfMOR) in morphine-induced regulation of miR-133b, which depends on ERK1/2, (3) that morphine regulates miR-133b in hippocampal neurons, and (4) the role of delta opioid receptors in morphine-induced regulation of miR-133b. We conclude that the control of miR-133b levels may be a mechanism for the development of addiction to morphine, or other drugs of abuse that increase dopaminergic levels in the extracellular space. These results show that miR-133b is a possible new target for the design of new treatments against addictive disorders.

Keywords: addiction; dopaminergic system; miR-133b; miRNA; morphine; opioid; zebrafish.

Figure 1

(A) Duplex sequence of miR-133b, formed by 84 ribonucleotides. Mature miRNA is shown in red. (B) miR-133b inhibits the expression of transcription factor Pitx3, whose function is to activate the expression of tyrosine hydroxylase (TH), the dopamine transporter (DAT), the dopaminergic receptor (DRD2), the monoamine vesicular transporter type 2 (VMAT2), and the aldehyde deshydrogenase 2 (ADH2). These genes determine the neuronal differentiation to the dopaminergic phenotype, so that when miR-133b is expressed, the expression of the other genes is inhibited and hence, dopaminergic differentiation is blocked.

Figure 2

Schematic representation of the mechanism by which morphine regulates the differentiation of dopaminergic neurons through the control of the miR-133b expression and the transcription of the genes regulated by this miRNA (Pitx3, TH, and DAT). (A) Activation of ERK1/2 signaling by MOR reduces the expression of miR-133b, and hence increases the transcription level of its target, Pitx3. This transcription factor enhances the expression of TH and DAT. (B) Silencing MOR by specific morpholinos produces an increase in the expression of miRNA-133b, and reduces the transcription level of Pitx3, TH, and DAT. (C) Inhibition of ERK1/2, even when the MOR receptor is activated by morphine, produces the same effect as knockdown of the receptor, i.e., the expression of miR-133b increases, and hence, the expression of Pitx3, TH, and DAT decreases, which reduces the level of dopaminergic neuron differentiation.