Abstract
Prenatal exposure to cocaine, in mammals, has been shown to interfere with the expression of opioid receptors, which can have repercussions in its activity. Likewise, microRNAs, such as let-7, have been shown to regulate the expression of opioid receptors and hence their functions in mammals and in vitro experiments. In light of this, using the zebrafish embryos as a model our aim here was to evaluate the actions of cocaine in the expression of opioid receptors and let-7d miRNA during embryogenesis. In order to determine the effects produced by cocaine on the opioid receptors (zfmor, zfdor1 and zfdor2) and let-7d miRNA (dre-let-7d) and its precursors (dre-let-7d-1 and dre-let-7d-2), embryos were exposed to 1.5 µM cocaine hydrochloride (HCl). Our results revealed that cocaine upregulated dre-let-7d and its precursors, and also increased the expression of zfmor, zfdor1 and zfdor2 during early developmental stages and decreased them in late embryonic stages. The changes observed in the expression of opioid receptors might occur through dre-let-7d, since DNA sequences and the morpholinos of opioid receptors microinjections altered the expression of dre-let-7d and its precursors. Likewise, opioid receptors and dre-let-7d showed similar distributions in the central nervous system (CNS) and at the periphery, pointing to a possible interrelationship between them.In conclusion, the silencing and overexpression of opioid receptors altered the expression of dre-let-7d, which points to the notion that cocaine via dre-let-7 can modulate the expression of opioid receptors. Our study provides new insights into the actions of cocaine during zebrafish embryogenesis, indicating a role of miRNAs, let-7d, in development and its relationship with gene expression of opioid receptors, related to pain and addiction process.
Highlights
Opioid effects are mediated by the m, d, and k-opioid receptors (MORs, DORs, and KORs, respectively) [1]
Taking into account all of the above aspects, we used the zebrafish as a model organism to determine the effects produced by cocaine in the expression of opioid receptors, let-7d miRNA and to study the interrelationship between let-7d and opioid receptors along embryonic development. In this investigation we report that the silencing and overexpression of opioid receptors altered the expression of miRNA dre-let-7d and their precursors, indicating a close relationship between them
Since the analgesia produced by morphine is mainly due to its interaction with the MOR [1], the changes induced by cocaine in MOR expression could induce alterations in its function [14,48] and in its analgesic activity
Summary
Opioid effects are mediated by the m-, d-, and k-opioid receptors (MORs, DORs, and KORs, respectively) [1]. When opioids are used over long periods of time, tolerance reduces the analgesic efficiency, and the opioid doses used must be raised for adequate levels of analgesia to be reached; this involves the risk of developing dependence and addiction to opioids [7,8]. These adverse effects of opioids noticeably affect their optimal use in the clinical treatment of chronic pain conditions [9]
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