Change in microRNAs associated with neuronal adaptive responses in the nucleus accumbens under neuropathic pain.
Neuropathic pain is the most difficult type of pain to control, and patients lose their motivation for the purposive pursuit with a decrease in their quality of life. Using a functional magnetic resonance imaging analysis, we demonstrated that blood oxygenation level-dependent signal intensity was increased in the ipsilateral nucleus accumbens (N.Acc.) following peripheral nerve injury. microRNAs are small, noncoding RNA molecules that direct the post-transcriptional suppression of gene expression, and play an important role in regulating synaptic plasticity. In this study, we found that sciatic nerve ligation induced a drastic decrease in the expression of miR200b and miR429 in N.Acc. neurons. The expression of DNA methyltransferase 3a (DNMT3a), which is the one of the predicted targets of miR200b/429, was significantly increased in the limbic forebrain including N.Acc. at 7 d after sciatic nerve ligation. Double-immunolabeling with antibodies specific to DNMT3a and NR1 showed that DNMT3a-immunoreactivity in the N.Acc. was located in NR1-labeled neurons, indicating that increased DNMT3a proteins were dominantly expressed in postsynaptic neurons in the N.Acc. area under a neuropathic pain-like state. The results of these analyses provide new insight into an epigenetic modification that is accompanied by a dramatic decrease in miR200b and miR429 along with the dysfunction of "mesolimbic motivation/valuation circuitry" under a neuropathic pain-like state. These phenomena may result in an increase in DNMT3a in neurons of the N.Acc. under neuropathic pain, which leads to the long-term transcription-silencing of several genes.
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo 142-8501, Japan.
Satoshi
S
Imai
Mai
M
Saeki
Makoto
M
Yanase
Hiroshi
H
Horiuchi
Minako
M
Abe
Michiko
M
Narita
Naoko
N
Kuzumaki
Tsutomu
T
Suzuki
Minoru
M
Narita
D000222:Adaptation, Physiological / Q000502:physiology*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000378:metabolism; D006930:Hyperalgesia / Q000473:pathology; D007091:Image Processing, Computer-Assisted; D066298:In Vitro Techniques; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D009714:Nucleus Accumbens / Q000098:blood supply / Q000473:pathology* / Q000503:physiopathology*; D010100:Oxygen / Q000097:blood; D012097:Repressor Proteins / Q000378:metabolism; D012585:Sciatica / Q000473:pathology*; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D000074165:Zinc Finger E-box Binding Homeobox 2
C513734:Abi1 protein, mouse; D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C000715535:Dnmt3a protein, mouse; C083480:Gpm6a protein, mouse; D018398:Homeodomain Proteins; C497393:Mecp2 protein, mouse; D008562:Membrane Glycoproteins; D051783:Methyl-CpG-Binding Protein 2; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; C494209:Snap25 protein, mouse; D050825:Synaptosomal-Associated Protein 25; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D010100:Oxygen