PMID- 33806698
OWN - NLM
STAT- MEDLINE
DCOM- 20210422
LR  - 20211204
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 22
IP  - 5
DP  - 2021 Mar 4
TI  - NFAT5 Deficiency Alleviates Formalin-Induced Inflammatory Pain Through mTOR.
LID - 10.3390/ijms22052587 [doi]
LID - 2587
AB  - Nuclear factor of activated T cells (NFAT5) is a well-known transcription factor 
      that regulates the expression of genes involved in osmotic stress. However, the 
      role of NFAT5 in inflammatory pain remains unknown. Here, we studied the function 
      of NFAT5 in inflammatory pain using NFAT5-heterozygous (Het) mice. To study 
      inflammatory pain, we injected 10 microL of 2% formalin into the right hind paws of 
      mice and monitored pain behaviors, such as licking, lifting, and flinching, for 
      60 min. After the first 15 min (phase I), there were no significant differences 
      in pain behaviors between wild-type (WT) and NFAT5-Het mice. However, from 15-60 
      min (phase II), NFAT5-Het mice displayed significantly fewer pain behaviors 
      compared to WT mice. Further, the expression levels of inflammatory-pain-related 
      factors, including c-Fos, phosphorylated extracellular signal-regulated kinase 
      (p-ERK), and phosphorylated n-methyl-D-aspartate receptor subunit 2B (p-NR2B), 
      were significantly elevated in the spinal dorsal neurons of formalin-treated WT 
      mice but was not elevated in NFAT5-Het mice. Similarly, c-Fos, p-ERK, and p-NR2B 
      levels were significantly higher in glutamate-treated PC12 neuronal cells but 
      were not affected by Nfat5 silencing in glutamate-treated PC12 cells. Altogether, 
      our findings suggest that NFAT5 deficiency may mitigate formalin-induced 
      inflammatory pain by upregulating mammalian target of rapamycin (mTOR) expression 
      and downregulating its downstream factors in spinal dorsal neurons. Therefore, 
      NFAT5 is a potential therapeutic target for the treatment of inflammatory pain.
FAU - Gwon, Do Hyeong
AU  - Gwon DH
AD  - Department of Medical Science, School of Medicine, Chungnam National University, 
      Daejeon 35015, Korea.
AD  - Department of Anatomy, Brain Research Institute, School of Medicine, Chungnam 
      National University, Daejeon 35015, Korea.
FAU - Kim, Song I
AU  - Kim SI
AD  - Department of Medical Science, School of Medicine, Chungnam National University, 
      Daejeon 35015, Korea.
AD  - Department of Anatomy, Brain Research Institute, School of Medicine, Chungnam 
      National University, Daejeon 35015, Korea.
FAU - Lee, Seoung Hun
AU  - Lee SH
AD  - Department of Anesthesiology and Pain Medicine, School of Medicine, Chungnam 
      National University, Daejeon 35015, Korea.
FAU - Noh, Chan
AU  - Noh C
AD  - Department of Anesthesiology and Pain Medicine, School of Medicine, Chungnam 
      National University, Daejeon 35015, Korea.
FAU - Kim, Yeojung
AU  - Kim Y
AUID- ORCID: 0000-0002-2079-670X
AD  - Department of Anesthesiology and Pain Medicine, School of Medicine, Chungnam 
      National University, Daejeon 35015, Korea.
FAU - Yun, Sangwon
AU  - Yun S
AD  - Department of Anesthesiology and Pain Medicine, School of Medicine, Chungnam 
      National University, Daejeon 35015, Korea.
FAU - Lee, Won Hyung
AU  - Lee WH
AD  - Department of Anesthesiology and Pain Medicine, School of Medicine, Chungnam 
      National University, Daejeon 35015, Korea.
FAU - Oh, Jun Young
AU  - Oh JY
AD  - Department of Neuroscience and Physiology and Dental Research Institute, School 
      of Dentistry, Seoul National University, Seoul 08826, Korea.
FAU - Kim, Dong Woon
AU  - Kim DW
AUID- ORCID: 0000-0001-7691-1394
AD  - Department of Medical Science, School of Medicine, Chungnam National University, 
      Daejeon 35015, Korea.
AD  - Department of Anatomy, Brain Research Institute, School of Medicine, Chungnam 
      National University, Daejeon 35015, Korea.
FAU - Hong, Jinpyo
AU  - Hong J
AUID- ORCID: 0000-0002-4776-4396
AD  - Department of Neuroscience and Physiology and Dental Research Institute, School 
      of Dentistry, Seoul National University, Seoul 08826, Korea.
FAU - Lee, Sun Yeul
AU  - Lee SY
AUID- ORCID: 0000-0002-6124-5138
AD  - Department of Anesthesiology and Pain Medicine, School of Medicine, Chungnam 
      National University, Daejeon 35015, Korea.
LA  - eng
GR  - NRF-2020R1C1C1005423, 2020R1I1A1A01060928/National Research Foundation of Korea/
GR  - 2018-CF-019/Chungnam National University Hospital Research Fund/
PT  - Journal Article
DEP - 20210304
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Nfat5 protein, mouse)
RN  - 0 (Transcription Factors)
RN  - 1HG84L3525 (Formaldehyde)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Formaldehyde/*pharmacology
MH  - Inflammation/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Neurons/metabolism
MH  - PC12 Cells
MH  - Pain/*chemically induced/*metabolism
MH  - Pain Measurement/methods
MH  - Rats
MH  - Spinal Cord/metabolism
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Transcription Factors/*metabolism
MH  - Up-Regulation/physiology
PMC - PMC7961436
OTO - NOTNLM
OT  - ERK
OT  - NFAT5
OT  - NR2B
OT  - c-Fos
OT  - inflammatory pain
OT  - mTOR
COIS- The authors declare no conflict of interest.
EDAT- 2021/04/04 06:00
MHDA- 2021/04/23 06:00
PMCR- 2021/03/04
CRDT- 2021/04/03 01:24
PHST- 2021/02/04 00:00 [received]
PHST- 2021/02/25 00:00 [revised]
PHST- 2021/03/01 00:00 [accepted]
PHST- 2021/04/03 01:24 [entrez]
PHST- 2021/04/04 06:00 [pubmed]
PHST- 2021/04/23 06:00 [medline]
PHST- 2021/03/04 00:00 [pmc-release]
AID - ijms22052587 [pii]
AID - ijms-22-02587 [pii]
AID - 10.3390/ijms22052587 [doi]
PST - epublish
SO  - Int J Mol Sci. 2021 Mar 4;22(5):2587. doi: 10.3390/ijms22052587.