PMID- 27818163
OWN - NLM
STAT- MEDLINE
DCOM- 20180112
LR  - 20231213
IS  - 1872-9754 (Electronic)
IS  - 0197-0186 (Linking)
VI  - 101
DP  - 2016 Dec
TI  - Down-regulation of zinc transporter-1 in astrocytes induces neuropathic pain via 
      the brain-derived neurotrophic factor - K(+)-Cl(-) co-transporter-2 signaling 
      pathway in the mouse spinal cord.
PG  - 120-131
LID - S0197-0186(16)30161-9 [pii]
LID - 10.1016/j.neuint.2016.11.001 [doi]
AB  - We previously demonstrated, using a DNA microarray analysis, the down-regulated 
      expression of the slc30a1 gene (zinc transporter 1, ZnT1) in a neuropathic pain 
      model induced by partial sciatic nerve ligation (PSNL). Zinc is an essential 
      trace mineral that plays important roles in physiological functions, and ZnT1 
      modulates intracellular zinc levels. In the present study, we examined the 
      effects of the down-regulation of the ZnT1 gene in the spinal cord on tactile 
      allodynia. The knockdown (KD) of ZnT1 by the intrathecal administration of siRNA 
      against ZnT1 to mice induced allodynia, a characteristic syndrome of neuropathic 
      pain, which persisted for at least one month. ZnT1 KD increased intracellular 
      zinc concentrations in primary astrocyte cultures, and this was followed by 
      enhanced PKCalpha membrane translocation and NFkappaB nuclear translocation as well as 
      increases in the levels of IL-6 and BDNF expressed and the phosphorylation of 
      CREB in vitro. Neuropathic pain induced by ZnT1 KD was inhibited by an IL-6, 
      BDNF, and TrkB siRNA injection. The down-regulated expression of KCC2 in spinal 
      cord was induced by ZnT1 KD and prevented by an intrathecal injection of IL-6, 
      BDNF, and TrkB siRNA. These results indicate that PSNL via the down-regulated 
      expression of ZnT1 increases intracellular zinc concentrations, enhances PKCalpha 
      membrane translocation and NFkappaB nuclear translocation, up-regulates the 
      expression of IL-6, increases the phosphorylation of CREB, and promotes the BDNF 
      cascade reaction in astrocytes, thereby down-regulating the expression of KCC2 
      and inducing neuropathic pain in vivo. This mechanism is considered to be 
      responsible for the activation of TrkB in neurons through the release of BDNF 
      from astrocytes. The results of the present study also indicate that zinc 
      signaling in astrocytes occurs upstream of the BDNF-TrkB-KCC2 cascade reaction.
CI  - Copyright A(c) 2016 Elsevier Ltd. All rights reserved.
FAU - Kitayama, Tomoya
AU  - Kitayama T
AD  - Department of Pharmacy, School of Pharmacy and Pharmaceutical Science, Mukogawa 
      Women's University, Hyogo 663-8179, Japan. Electronic address: 
      tomokita@mukogawa-u.ac.jp.
FAU - Morita, Katsuya
AU  - Morita K
AD  - Department of Pharmacology, Faculty of Nursing, Hiroshima Bunka Gakuen 
      University, 2-10-3 Agaminami, Kure-city, Hiroshima 737-0004, Japan. Electronic 
      address: morita@hbg.ac.jp.
FAU - Motoyama, Naoyo
AU  - Motoyama N
AD  - Department of Dental Science for Health Promotion, Division of Integrated Health 
      Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 
      Kasumi, Minami-ku, Hiroshima 734-8553, Japan. Electronic address: 
      motonao@hiroshima-u.ac.jp.
FAU - Dohi, Toshihiro
AU  - Dohi T
AD  - Department of Pharmacology, Faculty of Nursing, Hiroshima Bunka Gakuen 
      University, 2-10-3 Agaminami, Kure-city, Hiroshima 737-0004, Japan. Electronic 
      address: dohi@hbg.ac.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20161103
PL  - England
TA  - Neurochem Int
JT  - Neurochemistry international
JID - 8006959
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Symporters)
SB  - IM
MH  - Animals
MH  - Astrocytes/*metabolism
MH  - Brain-Derived Neurotrophic Factor/*metabolism
MH  - Down-Regulation/physiology
MH  - Hyperalgesia/metabolism
MH  - Male
MH  - Mice
MH  - Neuralgia/*metabolism
MH  - Neurons/metabolism
MH  - Sciatic Nerve/metabolism
MH  - Signal Transduction/physiology
MH  - Spinal Cord/*metabolism
MH  - Symporters/*metabolism
MH  - K Cl- Cotransporters
OTO - NOTNLM
OT  - Astrocyte
OT  - Neuropathic pain
OT  - Zinc ion
OT  - Zinc transporter 1
EDAT- 2016/11/08 06:00
MHDA- 2018/01/13 06:00
CRDT- 2016/11/08 06:00
PHST- 2016/06/14 00:00 [received]
PHST- 2016/11/02 00:00 [revised]
PHST- 2016/11/02 00:00 [accepted]
PHST- 2016/11/08 06:00 [pubmed]
PHST- 2018/01/13 06:00 [medline]
PHST- 2016/11/08 06:00 [entrez]
AID - S0197-0186(16)30161-9 [pii]
AID - 10.1016/j.neuint.2016.11.001 [doi]
PST - ppublish
SO  - Neurochem Int. 2016 Dec;101:120-131. doi: 10.1016/j.neuint.2016.11.001. Epub 2016 
      Nov 3.