MicroRNAs: emerging role in the endogenous μ opioid system

MicroRNAs (miRNAs) are small non-coding RNAs that function as translational repressors and represent an important element in tissue development as well as disease. MiRNA sequences and their target sites in mRNAs show an extensive degree of conservation across species. A single miRNA is now believed to recognize the 3'untranslated region of mRNAs in a sequence-specific manner to inhibit the protein expression of literally hundreds of targeted mRNAs. The human genome encodes more than 1000 miRNAs which target over 60% of mammalian and human transcripts. It is thus not surprising that expression changes in miRNAs can have a far-reaching impact on cellular functions, including the opioid system. Opioids, psychoactive chemicals that resemble morphine in their pharmacological effects are a class of potent analgesics used for treating various forms of acute and chronic pain. The mu opioid receptor is primarily responsible for opioid analgesia and anti-nociceptive tolerance. There is an ever-growing appreciation of miRNAs as important regulators of biological processes where opioids have an important impact, such as regulation of opioid receptors themselves. For example, a large number of splice variants of the primary transcript involve both 3' and 5' splicing of the mu opioid receptor mRNA, many of which can potentially be targeted by miRNAs. Conversely, miRNAs can be regulated by opioids. Two mu opioid receptor agonists, morphine and fentanyl, display differential mechanisms of signalling linked to specific miRNA expression. Moreover, miRNA - opioid connections impact on neuronal cell development, drug addiction, pain perception, neuroimmune system interaction and cell proliferation and tumorigenesis. These aspects will be the subject of this review.