title: MicroRNA 339 down-regulates μ-opioid receptor at the post-transcriptional level in response to opioid treatment.
abstract: μ-Opioid receptor (MOR) level is directly related to the function of opioid drugs, such as morphine and fentanyl. Although agonist treatment generally does not affect transcription of mor, previous studies suggest that morphine can affect the translation efficiency of MOR transcript via microRNAs (miRNAs). On the basis of miRNA microarray analyses of the hippocampal total RNA isolated from mice chronically treated with μ-opioid agonists, we found a miRNA (miR-339-3p) that was consistently and specifically increased by morphine (2-fold) and by fentanyl (3.8-fold). miR-339-3p bound to the MOR 3'-UTR and specifically suppressed reporter activity. Suppression was blunted by adding miR-339-3p inhibitor or mutating the miR-339-3p target site. In cells endogenously expressing MOR, miR-339-3p inhibited the production of MOR protein by destabilizing MOR mRNA. Up-regulation of miR-339-3p by fentanyl (EC(50)=0.75 nM) resulted from an increase in primary miRNA transcript. Mapping of the miR-339-3p primary RNA and its promoter revealed that the primary miR-339-3p was embedded in a noncoding 3'-UTR region of an unknown host gene and was coregulated by the host promoter. The identified promoter was activated by opioid agonist treatment (10 nM fentanyl or 10 μM morphine), a specific effect blocked by the opioid antagonist naloxone (10 μM). Taken together, these results suggest that miR-339-3p may serve as a negative feedback modulator of MOR signals by regulating intracellular MOR biosynthesis.
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Qifang
authors.initials: Q
authors.lastname: Wu
authors.forename: Cheol Kyu
authors.initials: CK
authors.lastname: Hwang
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: Yadav
authors.initials: Y
authors.lastname: Wagley
authors.forename: Hong-Yiou
authors.initials: HY
authors.lastname: Lin
authors.forename: Do Kyung
authors.initials: DK
authors.lastname: Kim
authors.forename: Ping-Yee
authors.initials: PY
authors.lastname: Law
authors.forename: Horace H
authors.initials: HH
authors.lastname: Loh
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Wei
mesh_terms: D020413:3' Untranslated Regions; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D005283:Fentanyl / Q000494:pharmacology; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D020413:3' Untranslated Regions; D000701:Analgesics, Opioid; D035683:MicroRNAs; D009292:Narcotic Antagonists; D012333:RNA, Messenger; D017450:Receptors, Opioid, mu; D009270:Naloxone; D009020:Morphine; D005283:Fentanyl