Role of non-coding RNAs in morphine function

Morphine is widely used in medicine to control moderate to severe pain. However, long-term administration of morphine is accompanied by unfavorable phenomena like tolerance and dependence to the drug. The exact molecular mechanisms underlying morphine tolerance and dependence have remained unclear. The effects of morphine are mediated via its binding to opioid receptors, which are distributed throughout the central and peripheral nervous systems. Further, data also indicates that alterations at other neurotransmitter receptors and downstream signaling pathways are also involved in morphine tolerance and dependence. Changes in gene expression have been reported in different brain areas, including the midbrain, striatum, hippocampus, and cortex following tolerance and addiction to morphine. However, central epigenetic changes during tolerance and addiction to morphine remain unclear. non-coding RNAs (ncRNAs) constitute the majority of the transcriptome in the brain and play essential roles in regulating cellular processes. ncRNAs are commonly linear molecules that are divided into housekeeping and regulatory subgroups. The former includes ribosomal (rRNA), transfer (tRNA), small nuclear (snRNA) and small nucleolar (snoRNA) RNAs that are ubiquitously expressed and contribute to structural and functional homeostasis. On the other hand, regulatory ncRNAs are involved in gene regulation and are typically divided into two categories based on their length. The first category includes RNAs with lengths fewer than ۲۰۰ nucleotides; these RNAs include micro-RNAs (miRNAs), small interfering RNAs (siRNAs), and RNAs associated with the Piwi protein or piRNAs. ncRNAs containing more than ۲۰۰ nucleotides are referred to as long ncRNAs (lncRNAs), which are involved in a variety of biological processes, including gene expression. It is also worth noting that circular RNAs (circRNAs) are a unique class of ncRNAs covalently-linked ends with having more than ۲۰۰ nucleotides that are produced due to a back-splicing process. Reports during the past two decades indicate the involvement of ncRNAs in addiction to morphine, alcohol, methamphetamine, cocaine, and heroin. Our data indicate the involvement of different miRNAs, including miR-۱۲۴, miR-۱۳۳, miR-۳۳۹, miR-۳۶۵. Others and we have also shown that changes in the expression of long non-coding RNAs such as BC۱, H۱۹, MALAT۱, and MIAT۱ as well as circular non-coding RNAs such as CircOprm۱ in different areas of the brain and spinal cord after morphine treatment in rats, which indicate the involvement of these RNAs in the effects of morphine. It can be concluded that the analgesic effects of morphine and its adverse effects such as addiction resulted from its repeated use are mediated by changes in the expression of various genes and non-coding RNAs have a significant role in the effects of morphine due to their regulatory role in regulating gene expression processes in the nervous system. Therefore, they should be given more attention in future research and their performance in morphine function needs further investigations.

کلیدواژه ها:

Pain management ، Tolerance ، Addiction ، Gene regulation ، non-coding RNAs