PMID- 27760212
OWN - NLM
STAT- MEDLINE
DCOM- 20170606
LR  - 20211204
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 11
IP  - 10
DP  - 2016
TI  - Down-Regulation of CXCL12/CXCR4 Expression Alleviates 
      Ischemia-Reperfusion-Induced Inflammatory Pain via Inhibiting Glial TLR4 
      Activation in the Spinal Cord.
PG  - e0163807
LID - 10.1371/journal.pone.0163807 [doi]
LID - e0163807
AB  - Toll-like receptor 4 (TLR4) is important for the pathogenesis of inflammatory 
      reactions and the promotion of pain processing after ischemia/reperfusion (IR) in 
      spinal cord. Recently, C-X-C chemokine ligand 12 (CXCL12) and its receptor, C-X-C 
      chemokine receptor 4 (CXCR4), were demonstrated to be simultaneously critical for 
      inflammatory reactions, thereby facilitating glial activation. However, whether 
      CXCL12/CXCR4 expression can contribute to IR-induced inflammatory pain via spinal 
      TLR4 remained unclear. A rat model was established by 8 min of aortic arch 
      occlusion. The effects of CXCL12/CXCR4 expression and TLR4 activation on 
      inflammatory hyperalgesia were investigated by pretreatments with 
      CXCL12-neutralizing antibody, CXCR4 antagonist (AMD3100) and TLR4 antagonist 
      (TAK-242) for 5 consecutive days before surgery. The results indicated that IR 
      induced significant and sustained inflammatory pain, observed as decreases in paw 
      withdrawal threshold (PWT) and paw withdrawal latency (PWL), throughout the 
      post-injury period. The increased levels of TLR4 and proinflammatory chemokine 
      CXCL12, as well as its receptor, CXCR4, were closely correlated with the PWT and 
      PWL trends. Double immunostaining further suggested that TLR4, which is mainly 
      expressed on astrocytes and microglia, was closely co-localized with CXCL12 and 
      CXCR4 in spinal dorsal horn. As expected, intrathecal pretreatment with the TLR4 
      antagonist, TAK-242 markedly ameliorated pain by inhibiting astrocytic and 
      microglial activation, as shown by decreases in TLR4 immunoreactivity and the 
      percentage of double-labeled cells. These protective effects were likely due in 
      part to the reduced production of the downstream cytokines IL-1beta and TNF-alpha, as 
      well as for the recruitment of CXCL12 and CXCR4. Additionally, intrathecal 
      pretreatment with CXCL12-neutralizing antibody and AMD3100 resulted in similar 
      analgesic and anti-inflammatory effects as those receiving TAK-242 pretreatment. 
      These results suggest that intrathecal blockade of CXCL12/CXCR4 expression may 
      attenuate IR-induced pain sensation and the release of inflammatory cytokines by 
      limiting glial TLR4 activation in spinal cord.
FAU - Li, Xiao-Qian
AU  - Li XQ
AD  - Department of Anesthesiology, First Affiliated Hospital, China Medical 
      University, Shenyang 110001, Liaoning, China.
FAU - Zhang, Zai-Li
AU  - Zhang ZL
AD  - Department of Anesthesiology, First Affiliated Hospital, China Medical 
      University, Shenyang 110001, Liaoning, China.
FAU - Tan, Wen-Fei
AU  - Tan WF
AD  - Department of Anesthesiology, First Affiliated Hospital, China Medical 
      University, Shenyang 110001, Liaoning, China.
FAU - Sun, Xi-Jia
AU  - Sun XJ
AD  - Department of Anesthesiology, First Affiliated Hospital, China Medical 
      University, Shenyang 110001, Liaoning, China.
FAU - Ma, Hong
AU  - Ma H
AD  - Department of Anesthesiology, First Affiliated Hospital, China Medical 
      University, Shenyang 110001, Liaoning, China.
LA  - eng
PT  - Journal Article
DEP - 20161019
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Benzylamines)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (Cxcr4 protein, rat)
RN  - 0 (Cyclams)
RN  - 0 (Heterocyclic Compounds)
RN  - 0 (Receptors, CXCR4)
RN  - 0 (Sulfonamides)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate)
RN  - S915P5499N (plerixafor)
SB  - IM
MH  - Animals
MH  - Astrocytes/drug effects/metabolism
MH  - Behavior, Animal/drug effects
MH  - Benzylamines
MH  - Chemokine CXCL12/*metabolism
MH  - Cyclams
MH  - Down-Regulation/drug effects
MH  - Heterocyclic Compounds/pharmacology
MH  - Hyperalgesia/complications
MH  - Inflammation/complications
MH  - Microglia/drug effects/*metabolism
MH  - Pain/complications/etiology/*metabolism/pathology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, CXCR4/antagonists & inhibitors/*metabolism
MH  - Reperfusion Injury/*complications
MH  - Spinal Cord/drug effects/*metabolism/pathology
MH  - Sulfonamides/pharmacology
MH  - Toll-Like Receptor 4/antagonists & inhibitors/*metabolism
PMC - PMC5070836
COIS- The authors have declared that no competing interests exist.
EDAT- 2016/10/21 06:00
MHDA- 2017/06/07 06:00
PMCR- 2016/10/19
CRDT- 2016/10/21 06:00
PHST- 2016/04/13 00:00 [received]
PHST- 2016/09/14 00:00 [accepted]
PHST- 2016/10/21 06:00 [pubmed]
PHST- 2017/06/07 06:00 [medline]
PHST- 2016/10/21 06:00 [entrez]
PHST- 2016/10/19 00:00 [pmc-release]
AID - PONE-D-16-14450 [pii]
AID - 10.1371/journal.pone.0163807 [doi]
PST - epublish
SO  - PLoS One. 2016 Oct 19;11(10):e0163807. doi: 10.1371/journal.pone.0163807. 
      eCollection 2016.