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Chi

n MedJ2006;119,
11)
.'
930—
938 


ReVI
■I
  ●
 
eW  
art
■I

 CI

 
e 

The i
m m une 
syst
em :a 
new 
look 
at pai
n 
ZHANG 
Jun・

hua 
and 
HUANG 
Yu・

guang 

Keywor
ds:pai
n;m echani
sm ;i
m m une;gl

a;neur
opat
hic 
pai
n 

obj
eet
ive
  To
 rev
iew 
the
 rel
ati
ons
hip 
bet
wee
n t
he 
immune
 sys
tem 
and 
he
t  
mec
hani
sm 
of 
pai
n. 
Dat
a sources  Rel
ated 
resear
ches
 publ
ished 
in 
h e 
t per
iod 
of 
1987-
- 2005 
wer
e s
yst
em at
ical
ly 
revi
ewed.
 
St
udy 
sel
ecti
on  Ar
ticl
es 
about
 h e 
t immune 
syst
em 
and 
pain 
were 
sel
ect
ed.
 
Dat
a extracti
on  Dat
a were mainl
y ext
ract
ed 
from 
74 ar
ticl
es which a
r e l
ist
ed i
n t
h e r
efer
ence sect
ion of 
this
 
revi
ew .
 
Resul
ts  Pai
n was
 cl
assi
cal
ly vi
ewed as
 bei
ng medi
ated sol
ely by neur
ons.However
,growi
ng evi
dence has
 

howed 
h e possi
t ble 
rel
ati
onsh
i ps 
bet
ween 
h e i
t mmune sys
tem 
n d 
a h e cent
t ral
 nervous 
syst
em.I
n t
his
 art
icl
e.we 
revi
ewed t
he r
ole of 
h e 
t immune syst
em 
in t
h e devel
opment
 of 
pain,t
oget
h er 
wit
h t
h e i
mport
ance 
of 
h e gi
t la 
in 
hi
t s 
process.Thes
e indi
f ngs
 suggest
 a 
novel
 appr
oach t
o pa
in 
cont
rol
 in 
h e 
t fut
ure.
 
Concl
usi
ons  The 
im une 
sys
tem 
plays
 a 
pot
ent
ial
 but
 import
ant
 rol
e i
n t
h e 
devel
opment
 of 
pai
n. 
Chi
n Me
d J 
2oO6:11
9(11
 1:
93o.
938 

D 
ai
n 
can
 be
 de
fi
ned
 as
 an
 un
pl
eas
ant
 s
ens
ory
  phenom enon 
that
 ref
lect
s t
he 
changes 
in 
dor
sal
 hor
n 

  and  emot
ionaI
  exper
ience  associ
ated  wi
th  neur
onal
 exci
tabi
li
ty of
 the spi
nal
 cor
d by afer
ent
 
act
uaI
 or
 pot
enti
aI ti
ssue dam age or
 descr
ibed i
n  i
nput
s.A 
chai
n of
 neur
ons 
car
ries 
the 
pai
n message 

erms 
of 
such 
dam age.I
t i
s a 
response 
tri
gger
ed by  f
rom 
the 
inj
ur
y t
o t
he 
spi
nal
 cor
d.and 
then 
fr0m 
the 
noci
cept
ive  i
nput
s  fr
0m  t
he  peri
pher
y  t
hat
  are  spi
nal
 cor
d up 
to 
c0nsci
0usness 
in t
he 
brai
n. 

ransm i
tted cent
ral
ly t
o t
he spi
naI
 cor
d and t
hen 
ascend t
hrough the pal
eospi
not
hal
am i
c t
ract
s to  I
t i
s now 
recogni
zed 
that
 pai
n and 
its 
modul
ati
on 
are 

im bi
c st
ruct
ures.
  not sol
ely medi
ated by neur ons but al
so i
nvolved in 
neuroim mune i
nteracti
on.
3-5 The fi
rst i
dea about t
he 

dynam i
c i
nter
-rel
ati
onshi
ps of
 the centr
aI ner
v ous 
Pai
n can be cl
ini
cal
ly 
classi
fied as ei
ther
 noci
cept
ive 
syst
em and i
mm une syst
em ar
ose fr
0m st
udi
es on 
or
 neur
opat
hic。 al
though  i
n  pr
act
ice t
hese  may 
coexi
st.。Noci
cept
ive pai
n ari
ses fr
Om mechani
ca1
.  the cascade of
 event
s i
niti
ated  by exposur
e t
o 
str
essor
s.。The 
imm une 
syst
em i
s obvi
ousl
y i
nvol
ved 
chem i
caI
 or
 ther
m aI
 irr
itat
ion of
 peri
pher
al sensor
y 
especi
all
y  when  ner
v e  damage  i
s  due  t
o  an 
ner
ves(
e.g.
,af
ter
 sur
ger
y or
 tr
auma or
 associ
ated 
wi
th 
degener
ati
ve 
processes 
such
 aS 
0st
e0ar
fh 

iti
s1.
  i
nfect
ious pr
ocess such as her
pes
 zost
er or
 an 

Typi
cal
ly,t
he noci
cept
ive 
pai
n i
s descr
ibed 
as 
shar
p  aut
oim m une  condi
ti
on  such  as  Gui
ll
ain.
Bar
re 

and wel
lIocal
ized.However
.neur
opathi
c pai
n has  syndr
ome.And i
t i
s cr
uci
all
y i
m port
ant
 to not
e t
hat
 

qui
te di
fer
ent
 cl
ini
caI
 feat
ures wi
th poor
 Iocal
izat
ion  the i
m mune syst
em al
so i
nvol
ves i
n a com pl
etel
y 

and i
s def
ined as pai
n i
nit
iat
ed or
 caused by a  st
eri

e ner
ve i
njur
y,because 
the 
cel
lul
ar 
debr
is i
s a 
pot
ent
 im m une 
sti
m ul
us.Non-
neur
onaI
 cel
ls i
ncl
ude 
pr
im ar
y I
esi
on or
 dysf
unct
ion i
n the ner
vous syst
em 
such as post
-her
pet
ic neur
algi
a and pai
nfuI
 di
abeti
c 
Depar
tment
 of Anest
hes
iol
ogy,Peki
ng Uni
on M e
dical
 Col
lege 
neur
opathy.The 
neur
opathi
c pai
n i
s of
ten associ
ated 
Hos
pit
al,Chi
nes
e Ac
ade
my 
of 
Medi
cl 
a Sc
ienc
es,Be
iji
ng 
1 
007
30,
 
wi
th 
the appear
ance of
 abnormal
 sensor
y si
gns 
wit
h 
Ch
ina(
Zhang 
JH 
andHua
n gYG)
 
cl
ini
caI
 char
act
e r
isti
cS 
of 
all
odyni
a f
ai
p n as 
a r
esul
t 
of  Cor
respondence  t
o: Dr
. H UA NG  Yu—
gua
n g, Depar
tm ent
  of 

a st
imulus whi
ch does not normall
y provoke p
ain)  n es
A h esi
t ology,Pek
i ng Uni
on 
Medi
ca
l Col
lege 
Hospi
tal
,Ch
i nes
e 

and/or
 hyperal
gesia f
an increased response to a  Ac
ade
my o
f Me
dic
l Sc
a ien
ces
, Be
iji
ng 1
 
007
30, Ch
ina(
Tel

 
86—1
0—65295580.Fa
x:86—
10—
65295580.Emai
l:pumchhyg@ya
hoo.
 
st
imul
us 
whi
ch 
is 
nor
mal

y pai
nfu1
).
 
com.
ca.
) 
The st
udy was
 suppor
td  by a gra
e nt f
rom t
he Nat
iona
l Nat
ural
 
Pai
n i
s  gener
all
y  consi
der
ed  as
  pur
ely  neur
a  Sci
ence 
Foundaf
ion(
No.30371370).
 

© Chinese Medical Association Publishing House


Downloaded from mednexus.org on [March 20, 2023]. For personal use only.
Chi
nes
e M edi
caf
 Jour
naf
 2006;119(
11)
:930—
938  93l
 


m m une cel

s i
n t
he per
ipher
y and gl
ia wi
thi
n t
he  mol
ecul
es i
ncl
udi
ng NG F and TNF dur
ing W al
ler
ian 
br
ain and 
spi
nal
 cor
d.  degener
ati
on by Schwann 
cel
ls_
1I
 Zuo et
 aI
 

 2 
found 

hat
 mast
 cel
ls wer
e acti
vated i
n mo
d eI
 of
 par
tiaI
 

n or
der 
to 
identi
fy 
novel
 ther
apeut
ics 
for 
pai
n and,i
n  sci
ati
c ner
ve 
inj
ur
y.T 
and B 
cel
ls
 can 
also 
gener
ate 
par
ti
cul
a5 t
o desi
gn com pounds f
or cl
ini
cal
 use i
n  i
nfl
am mat
ory  cyt
oki
nes  and  chem oki
nes,
  and 

m echani
sm  based” t
reat
ment
  par
adi
gms, i

 is  contr
ibute to i
nnat
e i
m mune r
esponses.Moal
em et
 

m por
tant
 to under
stand t
he under
lyi
ng pat
hophy-
  aI
  char
act
eri
zed 
T-cel
Ii
nfi

trat
ion 
int
o i
njur
ed 
sci
ati
c 
si
ology 
of 
pai
n.  ner
v es  i
n  a  neur
opat
hic  m o
d e. The  medi
ator
s 
pr
oduced by i
m m une cel
ls may be necessar
y and 

mmune 
react
ion 
aft
er 
inj
ury  sufi
cient
 for
 si
ckness si
nce pr
eventi
ng t
hei
r acti
ons 
Pai
n  i
s  pr
esented  as  one  of
  m any  nat
ural
  by  r
ecept
or  ant
agoni
sts  can  bl
ock
  si
ckness 
consequences of
 per
ipher
al i
nfect
ion and i
njur
  r
esponses, wher
eas exogenous admi
nist
rat
ion of
 

m mune r
eact
ion i
s gener
all
y i
nit
iat
ed 
by per
ipher
al  t
hese pr
otei
ns 
can 
creat
e si
ckness r
esponse.
14 

nfect
ion and i
njur
y,i
ncl
udi
ng exposur
e t
o mi
crobi
al
 
cel
1 wal

 fragment
s or
 toxi
ns.i
rri
tant
 chemi
cal
s and  Some i
nvest
igat
ors1
5,1
6 bel

eve t
hat
 the expr
essi
on 
aut
oJmm une  r
eact
ion  or
  neuropat
hy. The  of
  pr
oinf
lam mat
ory  cyt
oki
nes  i
s  r
elated  t
o  t
he 
const
ell
ati
on of
 changes that
 resul
ts f
r0m such  act
ivat
ion of
 nucl
ear
 fact
or-
KB f
NF-
KB)
.The NF.
KB 

m m une  chal
lenges  i
s  so  cal
led  t
he  si
ckness  si
gnal
 tr
ansduct
ion pat
hway 
m edi
ates 
expr
essi
on 
of 

esponse,i
ncl
udi
ng physi
ologi
cal
 responses (
fever

  a  cer
tai
n  number
  of
  genes  that
  par
tici
pat
e  i
n 
al
ter
ati
ons i
n pl
asma i
ons t
o suppress m i
ner
als  i
nfl
am mat
ory and i
m mune pr
ocesses.
  i
ncl
udi
ng 

equi
red by bact
eri
a/vi
ruses 
to 
repl
icat
e.i
ncreases i
n  I
L-1,I
L-6,I
L-8,TNFe
(,dynor
phi
n,I
CAM ,VCAM ,et
c. 
whi
te bl
ood cel

 repl

cat
ion,i
ncr
eased sl
eep,et
c.)
,  Tr
auma wi
ll
 sti
m ul
ate t
he nucl
ear
 tr
ansl
ocati
on of
 
behavi
oraI
 responses f
decr
eased soci
aIi
nterac
tion  N 
F-KB. act
ivat
e  thi
s  tr
anscri
pti
on  f
act
or,
’0  t
hus 
and  expl
orati
on, decr
eased  sexuaI
  act
ivi
ty.
  pr
omot
e the 
expressi
on o
f i
m mune 
factor
s.I
nhi
biti
on 
decr
eased  f
ood   and  wat
er i
ntake, et
c.)
, and  of
 the nucl
ear t
ransl
ocat
ion of
 NF-
KB wi
lI
 at
tenuat
e 
hor
m onaI
 responses fi
ncr
eased r
elease of
 cl
assi
c  t
he pai
n t
hat
 induced 
by 
dynor
phi
n.1
 
5 
hypot
hal
amo-

pit
uit
ary-

adr
enal
  and  sym pat
heti
c 
hor
mones)
.  I
m m une 
factors 
ent
eri
ng 
the centraI
 nervous 
syst
em 
The si
ckness r
esponse r
esul
ts 
frOm i
m m une.
to.br
ain  I
m munocyt
es  mi
grat
e  fr
om  t
he  ci
rcul
ati
on  t
o 

com m uni
cat
ion  i
niti
ated  by  pr
oinf
lamm at
ory  i
nfl
amed t
issues i
n mul
tipl
e st
eps. i
ncl
udi
ng t
hei
r 

cyt
oki
nes r
eleased by act
ivat
ed i
mm une cel
ls.As a  r
oll
ing, adhesi
on, and t
ransm i
grat
ion
 thr
ough
 the 

gr
oup, t
hese  pr
oinf
lamm at
ory  cyt
oki
nes  i
ncl
ude  vessel
  wal
1. Thi
s  i
s  or
chestr
ated  by  adhesi
on 
mol
ecul
es on l
eukocyt
es and vascul
ar 
endothel
ium .
 
nerve growt h factor ( NGF), nit
ric
 oxi de ( N0),
 
prostanoi
ds,interl
euki n-1(1
L-1)
,interl
eukin-6(IL.
6),
  I
nter
cel
lul
ar 
adhesi
on mol
ecul
e-1(
ICAM一
1 or
 CD54)
 

s expressed by 
endothel
ium 
and medi
ates adhesi
on 
and tumor necr
osis factor(
TNF) .Neutrophil
s ar
e t
he 
ear
liest
 inf
lam mat
ory 
cel
ls 
inf
il
trati
ng 
tissues 
fr0m 
the  and extr
avasati
on of
 leukocyt
es.Study has shown 

bl
ood .Per
kins et
 al
 found that
 neut
rophi
ls coul
d  t
hat
 ICAM-
1  r
egul
ates  t
he  hom i
ng  of
  opi
oid.
 

nvade  i
nto the  dam aged  ner
v e  and  pr
o duced  producing cell
s and the subsequent
 generati
on of
 
analgesia 
withi
n si
tes 
of pai
nfuIi
nfl
am mat
ion.1
9 
var
ious i
nfl
am m at
ory 
fact
ors i
ncl
udi
ng l
ipoxygenase 
pr
oduct
s,NO ,cyt
oki
nes,and chem oki
nes.NGF i
s a 
wel
l-est
abl
ished i
nfl
am mat
ory  medi
ator
,  of
 whi
ch  The 
proi
nfl
amm at
ory 
cyt
oki
nes r
eleased by 
act
ivat
ed 

he 
hyper
algesi
c act
ion
 seems 
to 
depend,i
n par
t,on  i
m mune 
cel

s ar
e l
arge 
prot
eins 
and 
unl
ikel
y t
o cr
oss 
neutr
ophi

 accum ul
ati
on.
 … I
n damaged per
ipher
aI  t
he 
blood-
brai
n bar
rier
 in 
a si
gni
fi
cant
 amount
.Ther
e 
ner
ves, as
 in  ot
her
 ti
ssues, m acr
ophages  ar
e  ar
e som e t
heor
ies 训 now t
yi
r ng t
o expl
ain t
he 

ecr
uit
ed by chemot
a ct
ic m ol
ecul
es.M acr
ophages  i
m mune.
to-
brai
n comm uni
cat
ion.
 
can r
elease many i
nfl
amm at
ory  medi
ator
s,not
a bl
y 
pr
o-i
nfl
ammat
ory 
cyt
oki
nes(
TNFo
(,I
L-1
 p)
,NG 
F,NO  Usi
ng i
ntr
aper
it
oneal
 admi
nist
rat
ion of
 pat
hogeni
c 
and  pr
o st
anoi
ds.
  Mor
eover
,  I
L-1
  wi
lI
  i
n  t
urn  agent
s,some r
esear
cher
s f
ound 
that
 si
gnal
s t
o t
he 
upr
egul
ate t
he  synt
hesi
s of
 a  r
ange  of
  pot
ent
  br
ain appear
 to 
be 
car
ried 
via 
the 
subdi
aphr
agm at
ic 

© Chinese Medical Association Publishing House


Downloaded from mednexus.org on [March 20, 2023]. For personal use only.
932  Chi
n Med 
J 2006;1
19(
11)
.'
930—
938 

vagus because (
1) pat
hogeni
c agent
s act
ivat
e  ci
rcum ventr
icul
ar 
organs。i
.e.t
he cyt
oki
nes ar
e abl
e 
sensor
y vagal
 neur
ons,as suppor
ted by i
ncr
eases 
in  t
o enter
 the brai
n i
n r
egi
ons wher
e t
he bl
ood—br
ain 
cFos。an i
m medi
ate-ear
ly gene pr
oduct
 used as a  barr
ier
 is absent
 or
 weak.and upon entr
y i
nto the 
neur
onaI
  acti
vat
ion  mar
ker
. expr
essi
on  i
n these  br
ain。cyt
oki
nes acti
vate neur
aI syst
ems t
hat
 then 

cel

s,  and (
2)subdi
aphr
agmat
ic vagot
omy bl
ocks  pr
oject
 to 
dis
tant
 t
arget
 regi
ons
 al

eri
ng 
thei
r 
act
ivi
ty 
hyper
algesi
a i
nduced by endot
oxi
n,I
L一1,and tumor  vi
a the r
elease of
 tr
adi
ti
onaI
 neur
otr
ansm i
tter
s;and 
necr
osi
s f
act
or.
 。。
  Acti
vat
ion of
 the sensor
y vagus  (
3)bi
ndi
ng t
o r
ecept
ors i
n t
he bl
ood vessel
s t
hat
 
may be secondar
y  t
o t
he acti
vat
ion of
 speci
ali
zed  cour
se through t
he br
ain. whi
ch wi
lI
 induce the 
sensor
y  st
ructur
es  cal
led  paragangl
ia.
  They  pr
oduct
ion of
 secondar
y messenger
s,t
hen di
fuse 
express I
L-1
 bi
ndi
ng si
tes and ar
e known t
o f
cIr
m  i
nto t
he br
ain 
and al
ter
 neur
aI act
ivi
ty.
 
afer
ent
 synapses onto sensor
y vagal
 fi
ber
s.The 
pathway by whi
ch abdom i
nal
 pat
hogeni
c si
gnal
s  I
m m une 
factors j
nduci
ng 
pai
n 
el
ici
t  hyperal
gesi
a  has  been  at
 Ieast
  par
tial
ly  I
t i
s r
eal
ized that
 the i
m mune syst
em pl
ays an 
expl
ained i
n the centr
aI ner
v ous syst
em by these  i
mpor
tant
 rol
e  i
n  t
he  i
rri
tat
ion  of
  pai
n.  Many 
studi
es.
  resear
ches tr
y  to expl
ain t
he devel
opment
 of
 pai
n. 
Som e  mechani
sms of
  neur
opathi
c  pai
n  i
ncl
ude 
M any studi
es ar
e r
elat
ed t
o t
he di
rect
 act
ion of  per
ipher
al mechani
sms:(
1)ect
opi
c di
schar
ges and 
m edi
ator
s on noci
cept
ive 
ter
minal
s t
hat
 inner
vat
e the  epha.
pti
c conduct
ion,(
2) col
lat
eral
 spr
out
ing,(
3) 

nfl
amed t
issues.These neur
ons expr
ess r
ecept
ors  coupl
ing bet
ween t
he sym pat
het
ic ner
vous syst
em 


or TN 
F’I
L-1,NG 
F’I
L.6,LI
 
F’hi
stami
ne,br
adyki
nin  and 
the sensor
y ner
vous
  syst
em,(4)bradyki
nin;and 
and pr
ost
anoi
ds.For
 exampl
e,br
adyki
nin 
act
s on B2  cent
raI
  mechanisms: (1) spinaI
  cor
d—anat
omi caI
 
recept
ors  on  noci
cept
ors.
  Tr
ansi
ent
  recept
or  r
e—or
gani
zat
ion,(
2)spi
nal
 cor
d—hyper
exci
tabi
li
ty,(
3) 
pot
ent
iaI
 cat
ion channel
。subf
ami

y v'member
 1  endogenous 
opi
oid 
and cannabi
noi
d systems.
 


TRPV1)
  channel
s  ar
e  al
so  sensi
ti
zed  by 
bradyki
nin.
 。 whi
ch mi
ght
 account
 for
 br
adyki
nin-
  M any studi
es concent
rat
e on t
he r
ole of
 imm une 

nduced heat
 sensi
ti
zat
ion.Pr
ost
agl
andi
ns act
 on a  f
act
ors 
in 
the 
occur
rence 
of 
pai
n.For
 TN 
F’I
L一1,I
L一6,
 
ser
ies
 of
 pr
ost
anoi
d r
ecept
ors(
E  DP and I
P)on  NGF and  pr
ost
agl
andi
n  E2  (
PGE2)
.ther
e i
s 
noci
cept
ors. They acti
vat
e adenyl
ate cycl
ase i
n  consi
der
abl
e evi
dence t
hat
 they  ar
e  pr
esent
 in 

hese neur
ons。el
evat
ing t
he concentr
ati
on of
 cAM  i
nfl
amm at
ory exudat
es;t
hey can pr
oduce pai
n or
 
whi
ch sensi
ti
zes ner
ve 
term i
nal
s. 。Thi
s m i
ght
 be 
the  hyper
algesi
a  when  i
rri
tant
s  ar
e  exogenousl
y 
reason  f
or  t
he  good  anal
gesi
c  pr
oper
ties  of  adm i
nist
ered t
o ani
mal
s and humans; and, most
 
cycl
ooxygenase  i
nhi
bit
ors  i
n  i
nfl
am mat
ory  pai
n.  i
mpor
tantl
y,ant
agoni
sm or
 neutr
ali
zat
ion of
 these 

Pr
otease—
act
ivat
ed 
recept
ors(
尸ARs)mi
ght
 be 
a new  f
act
ors r
educes pai
n  and  hyper
algesi
a i
n many 
m echani
sm  of
  noci
cept
or  sensi
ti
zat
ion.
  Mast  ani
maI
 model
s of
 inf
lammat
ion (
as bel
ow)
.Thus,
 
cel
l—deri
ved t
rypt
ase can decom pose speci
fi
c PAR  t
hese 
cyt
oki
nes can 
be 
both necessar
y and 
sufi
cient
 

esi
dues i
n t
he ami
no(
N)一
ter
minal
 domai
n。t
her
eby  f
or  pathogen—
induced  hyper
algesi
a  t
o  occur
. 
exposi
ng a noveI
 N ter
minus that
 functi
ons as a  Benne ̄Ju r
epor
ted a new modeI
 of
 inf
lam mat
ion i
n 

ethered  I
igand  t
o  act
ivat
e  t
he  r
ecept
or. W hen  whi
ch a f
ocaI
 neu 
ri
ti
s was pr
oduced i
n t
he r
at 
sci
ati
c 
act
ivat
ed,the PAR si
gnal
ing pathway can not
 onl
y  ner
v e. The r
esul
t suggest
ed the pr
esence of
 a 

nduce the pr
oduct
ion of
 m or
e cl
assi
caI
 al
gogens  neur
oim m une i
nter
act
ion that
 occur
s at
 the onset
 of
 
such  as  PGE2, but
  al
so  sensi
ti
ze  noci
cept
ive  ner
ve i
njur
y and cont
ri
but
es t
o t
he devel
opment
 of
 

ermi
nal
s by 
act
ing 
on 
TRPV1
 channel
s.  Oh
 et
 al
  neur
opat
hic pai
n.Hyper
algesi
a i
s pr
oduced bot
h by 

epor
ted t
hat
 m any chem oki
nes coul
d i
ncrease the  i
ntraperi
toneaI
 adm i
nist
rat
ion of
 the cel
1 wal
ls of
 
cal
cium cOncentr
ati
On i
n cuI
tur
ed DRG neur
ons and  gr
am—
negat
ive  bact
eri
a  (
endot
oxi
n;  al
so  cal
led 
al
so  st
im ul
ated  t
he  r
elease  of
  subst
ance  I
ipopoI
ysaccha 

ide)
 。 and by i
ntr
aper
it
oneal
 li
ve 
suggesti
ng 
dir
ect
 recept
or-medi
ated 
acti
ons.
  bacter
ia。
  both of
 whi
ch ar
e known t
o el
ici
t the 
rel
ease of
 pr
oinfl
amm at
ory cyt
oki
nes f
r0m a var
iet
y 

Ot
her
 mechani
sms
 bei
ng ar
gued t
o al

ow bl
ood-
  Of
 im m une cel
ls.
 

bor
ne 
c ̄oki
nes
 to 
reach 
tar
get
 r
ecept
ors
 in 
the 
brai
n 
Shu et
 al
∞ the fi
rst
 to descr
ibe t
he l
ink bet
w een 

ncl
ude (
1) act
ive  t
ranspor
t; (
2) cr
ossi
ng  at
  ,

© Chinese Medical Association Publishing House


Downloaded from mednexus.org on [March 20, 2023]. For personal use only.
Chi
nese
 M edi
caf
 Jour
naf
 2006;119(
11)
."
930—
938  933
 

NGF 
and pai
n.pr
esent
ed 
the r
esul
ts of
 exper
im ents  consi
der
abl
e  evi
dence  f
or  i
ts  i
nvol
vement
  i
n 
per
for
m ed  i
n  t
hei
r  l
abor
ator
y,  i
dent
ifi
ed  t
he  neur
opat
hic pai
n. Sever
aI st
udi
es have shown a 
m echani
sms  under
lyi
ng  t
he  i
nit
ial
  hyper
algesi
c  corr
elat
ion bet
ween the I
eveI
 of
 TN 
F expr
essi
on and 
response  t
o  NGF  The  i
niti
aI  hyper
algesi
a  i
n  t
he devel
opm ent
 of
 al
lodyni
a or
 hyper
algesi
a i
n 
response t
o syst
em i
c or
 peri
pher
all
y admi
nist
ered  neur
opat
hic pai
n model
s. ’
  The devel
opment
 of
 
NGF depends on i
ndi
rect
 m echani
sms.speci
fi
cal
ly  al
lodyni
a or
 hyper
algesi
a can be i
ncr
eased by the 
m ast
 cel
I  degr
anul
ati
on. They pr
esent
ed  r
ecent
  endoneur
iaI
  admi
nistr
ati
on  of
  TNF,
  wher
eas 
evi
dence i
ndi
cat
ing that
 NG F al
so i
s capabl
e of
  ant
agoni
sm of
 TNF has t
he opposi
te efect.
 一 
pot
ent
iat
ing capsai
cin-
evoked cur
rent
s i
n i
sol
ated  Benet
t  I
ooked  i
nto  t
he  contr
ibut
ion  of
  the 
sensor
y neur
ons.Uti
li
zing 
thi
s i
ntr
igui
ng obser
vat
ion.
  i
nfl
am mat
ory  r
esponse al
one on the product
ion of
 

hey pr
esent
ed a modeI
 that
 woul
d account
 for
 the  neuropat
hic pai
n.He f
ound t
hat
 usi
ng a speci
fi
c 

nit
iaI
  NGF-i
nduced  thermaI
  hyper
algesi
a. Other
  i
nhi
bit
or 
of 
the 
synt
hesi
s of
 TNFo
(or
 cycl
ospor
in.
A f
a 
st
udi
es ar
e t
yi
r ng to expl
ain t
he al
gesi
c efect
s of
  br
oad-
spect
rum i
mm unosuppressor
1 wi
lI
 reduce the 
NG F。 They  f
ound  t
hat
 the  hi
gh.
afi
nit
y  NGF  r
esponse t
o neur
opat
hic pai
n.I
n recent
 year
s,the 

ecept
ors(
tyr
osi
ne ki
nase r
ecept
or A,Tr
kA)wer
e  i
m por
tance  of
  TNF  i
n  pai
n  r
eli
ef  has  been 
expr
essed by about
 50% of
 noci
cept
ors and t
hei
r  under
scor
ed by t
he t
rem endous success of
 TNF 
acti
vati
on I
ed 
to phosphor
ylat
ion and sensi
ti
zati
on of
  ant
ibodi
es or
 neut
ral
izi
ng r
eagent
s f
or 
the 
treatment
 
TRPV1
  r
ecept
ors.
  whi
ch  m i
ght
  account
  f
or  of
 many autoi
m mune di
sor
der
s,i
ncl
udi
ng psor
iasi
s, 
NG F-
induced heat
 hyper
algesi
a.Anot
her
 impor
tant
  psori
ati
c ar
thri
ti
s, ankyl
osi
ng  spondyl
iti
s, Cr
ohn‘
s 
acti
on of
 NG F i
s i
ts modul
ati
on of
 noci
cept
or gene  di
sease. and r
heumat
oid ar
thr
iti
s. ,
 。 TNF mi
ght
 
expr
essi
on such as TRPV1,P2X3,Nav 1.
8,brai
n.  al
so  act
  di
rect
ly  on  TN 
F  r
e cept
ors  t
hat
  ar
e 
der
ived 
neur
otr
ophi
c f
act
or(
BDNF)and 
subst
ance 
P  expressed by noci
cept
ors 
to pr
oduce 
sensi
ti
zat
ion.
 
af
ter
 retr
ogr
ade 
transpor
t of
 NGF.
TrkA 
to t
he 
nucl
eus  Ner
ve i
njur
y al
so I
eads t
o i
ncr
eased expr
essi
on of
 
whi
ch  m i
ght
  underl
ie  i
ncr
eases  i
n  I
ong.
term  TN 
F  r
ecept
ors  1
  and  2  by  damaged  sensor
y 
noci
cept
or 
sensi
ti
vit
Y.  neur
ons.
  Fi
nal
ly,pr
e-empt
ive (
but
 not
 del
ayed)
 

reat
ment
 wi
th 
etaner
cept(
a TNF—
sequest
eri
ng 
drug)
 
Thom pson et
 aI
  summ ar
ized a gr
owi
ng par
t of
 dat
a  can  i
nhi
bit
  mechani
caI
  al
lodyni
a  i
n  neur
opathi
c 


m pl
icat
ing  a  cri
ti
caI
  r
ole  f
or  br
ain  der
ived  m odel
s. whi
ch i
ndi
cat
es t
hat
 TNF i
s par
ticul
arl
y 
neu 
rotr
ophi
c  f
act
or i
n  t
he  al
ter
ed  noci
cepti
ve  i
mpor
tant
 in t
he i
niti
ati
on of
 neur
opat
hic 
pai
n.4
u’ 

pr
ocessi
ng obser
v ed i
n t
he pr
esence 
of 
infl
am mat
ion 
Br
ain der
ived neur
otr
ophi
c f
act
or 
appear
s t
o f
unct
ion  I
L-1
 is a potent
 pr
o-i
nfl
am mat
ory cyt
oki
ne that
 is 
as a neur
otr
ansm i
tt
er/neur
omodul
ator
 in t
he dorsaI
  i
nvol
ved  i
n  neur
opathi
c  pai
n.  I
ntr
athecaI
 
hor
n of
 the 
spi
naI
 cor
d.wher
e i
t i
s r
eleased 仃0m the  adm i
nist
rati
on of
 IL-1
  can I
ead t
o sympt
oms of
 
cent
raI
 ter
minal
s  of
  sm al
1.cal
iber
  afer
ent
s  and  neur
opat
hic pai
n i
n heal
thy r
ats.
  The expr
essi
on of
 

ncr
eases 
the 
exci
tabi

iy 
t of
 dor
saI
 hor
n neu 

ons.
  I
L-1
  i
s  upr
egul
ated  af
ter
  ner
ve  i
niun,

  and 
neutr
ali
zing ant
ibodi
es  t
o  I
L-1
 recept
ors  r
educe 
NO i
s an i
m por
tant
 medi
ator
 of
 hyper
algesi
a and  pai
n-associ
ated  behavi
our
s i
n  mouse  model
s of
 

nduced i
n i
nfl
amed ti
ssues.probabl
y t
hrough bot
h  neur
opat
hy.
  However
.the mechani
sm of
 acti
on of
 

nduci
ble and neur
onaI
 ni
tri
c oxi
de synt
hase f
iNOS  I
L-1
 in t
he peri
pher
y i
s uncl
ear
. SeveraI
 studi
es 
and nNOS.r
espect
ivel
y).
  NO donor
s can i
nduce  i
ndi
cat
e t
hat
 the m echani
sm m i
ght
 be i
nvol
ved i
n a 
pai
n i
n hum ans∞ and NOS i
nhi
bit
ors can r
educe  com pl
ex  si
gnal
ing  cascade  that
 Ieads  t
o  t
he 

nfl
amm at
ory hyper
algesi
a i
n a PGE2.
dependent
  pr
oduct
ion of pr
0n0cicept
ive compounds(NO,NG  F,
 
m anner.
  Ant
agoni
sm of
 each of
 the medi
ator
s  pr
0st
agIandins,etc.
)fr0m immune cell
s or
 Schwann 
descr
ibed  above  pr
oduces  subst
anti
aI  anti
.  cel
ls. I
L-1
 mi
ght
 al
so di
rectl
y exci
te noci
cept
ive 
hyper
algesi
a wi
th hi
gh efi
cacy 
of 
pai
n r
eli
ef.
  fi
bres  or
 incr
ease thei
r r
esponses to heat
 sti
m uI

 


hrough an I L-
1 r ecept
or type I f
IL-1
 RI)/
protei
n 
TNF i
s consi
der
ed 
to be 
the 
prot
otype i
n the 
fami
ly 
of  t
yrosi
ne  ki nase  ( PTK)/
protei
n  ki nase  C 
pr
o-i
nfl
am mat
ory cyt
oki
nes.I
t i
nit
iat
es a cascade of
  fPKC)-dependent mechanism.  Hyperalgesia can 
acti
vat
ion
 of cytoki
nes and gr
owth f
act
ors (
for  be 
eli
cit
ed 
sim pl
y by 
adm i
nist
eri
ng 
either
 IL.1
 0r
 TNF 
example,
  NGF,  NO  and  PGE2). Ther
e  is  al
one;
  and t
he key i
m por
tance of
 pr
oinf
lam -
 

© Chinese Medical Association Publishing House


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934  Chi
n Med 
J 2006;119(
11).

930-
938 

m at
ory 
cyt
oki
nes i
n pathogeni
c hyper
algesi
a i
s cl
ear
  (
bot
h N.
met
hy1
.D.
aspar
tat
e(NMDA)and 
non-
NMDA 
仃Om the fact 
that
 it
 can be bl
ocked by ei
ther 
an I
 
L-1
  agoni
sts)
,IL-
1, I
L-6,TNF(
x, pr
ost
agl
andi
ns,and 
recept
or antagonist 
or 
TNF binding 
protein.
 ’'
  NGF.
0  A r
elevant
 study 。showed that
 intr
athecaI
 
adm i
nistr
ati
ons of
 CCL2  and  I
L-1
 induce  r
api
d 
There ar
e m any 
studi
es i
nvest
igat
ing t
he r
ole of
 IL-
6  act
ivati
on  and  r
ecr
uit
ment
 of
 macr
ophages  and 

n the  devel
opment
 of
  pai
n。 ’
。。 and  i
t i
s  wel

  mi
crogl
ia i
n t
he 
whi
te m ater
 of
 the spi
nal
 cor
d t
hat
 

evi
ewed  t
hat
 I 
L.6 r
elated t
o the devel
opm ent
 of
  i
s under
goi
ng W al
ler
ian degener
ati
on,whi
ch m i
ght,
 
pai
n and i
ntr
athecaI
 ant
i-I
L-6 
ant
ibody,ot
her
wise.w i
lI
  i
n turn,afect
 pai
n pr
ocessi
ng.
 
at
tenuat
e  t
his  r
eact
ion. M echani
caI
  al
lodyni
a  i
s 
cor
rel
ated wi
th 
the I
evel
s of
 IL-
6 i
m munor
eact
ivi
ty or
  Spi
naI
  cor
d  ast
rocyt
es  and  m i
crogl
ia  ar
e  key 
m RNA i
n t
he sci
ati
c ner
ve and DRG  r
espect
ivel
y,
  medi
ator
s of
 pat
hogen-i
nduced hyper
algesi
a.They 
af
ter
 ner
ve  const
ri
cti
on  i
njur
y.
  Compar
ed  wi
th  expr
ess  speci
fi
c  r
ecept
ors  f
or  some  i
nfecti
ous 
wi
ld-t
ype  mi
ce, t
her
m aI
  hyper
algesi
a  and  agent
s  I
ike  vari
ous  bact
eri
a  and  vi
ruses.
  For
 
m echani
caI
 al
lodyni
a wer
e I
ess i
n I
L一6一knockout
  exam pl
e.  gi
laI
  act
ivat
ion  wi
lI
  be  i
nduced  by 
mi
ce.
  The mechani
sm of
 IL-
6 act
ion i
s st
ilI
 not
 wel

  neur
otr
opi
c vi
rus(
that
 is,a 
vir
us 
that
 can “
home“t
o 
est
abl
ished.
  t
he br
ain
 and spi
naI
 cor
d1 such as H 

V-1
 that
 ar
e 
known 
to i
nvade t
he 
centr
aI ner
v ous syst
em .
  HI
V-1
 
Gl
ia:a m odul
ator
 of
 pai
n  i
nvades t
he br
ain and spi
nal
 cor
d ear
ly i
n. and 
Pai
n tr
ansm i
ts f
rOm t
he peri
pher
y t
o hi
gher
 br
ain  cont
inui
ng t
hroughout,di
sease pr
ogr
essi
on,
  and 
ar
eas.fr
Om w hi
ch pai
n messages can be ei
ther
  thi
s i
nvasi
on I
eads 
to 
the 
act
ivati
on 
of 
ast
rocyt
es 
and 
mi
crogl
ia.
  Tsuda et
 al
 。showed t
hat
 the acti
vat
ion 
suppr
essed  (
analgesia),
 relayed  unal
ter
ed,  or 
ampli
fi
ed (
hyperal
gesia).Pai
n modulati
on occur
s in  of
 m i
crogl
ia i
n neur
opathy r
equi
res P2X4 recept
ors,
 

he dor
saI
 horns 
of 
the spi
nal
 cor
d,wher
e per
ipher
al  whi
ch are upr
egul
ated and speci
fi
cal
ly 
expressed by 
ner
ves  r
elay  sensor
y  i
nformat
ion  t
o  pai
n  mi
crogl
ia  i
n  neur
opat
hic  pai
n  m odel
s. P2X7 

ransmi
ssi
on neur
ons f
PTNs)
.It
 is wher
e t
he  r
ecept
ors‘act
ivat
ion can I
ead t
o t
he pr
oducti
on and 
peri
pher
y meet
s t
he CNS t
hat
 both anal
gesi
a and  r
elease of
 inf
lam m at
ory  cyt
oki
nes. However
,the 
hyper
algesi
a ar
e cr
eat
ed.
  mi
ce 
wit
hout
 thi
s r
ecept
or 
show 
an 
impai
red 
abi
li
y 
t t
o 
devel
op  neur
opat
hic  pai
n.  A  r
ecent
  study 

Neur
ons ar
e not
 the onl
y cel
I t
ype i
nvol
ved i
n such  suggest
ed that
 TLR4 mi
ght
 contr
ibut
e t
o pai
nful
 

process.Rat
her
.spi
naI
 cor
d cel
ls cal
led “
gli
a“are  neuropat
hy.Thi
s r
ecept
or i
s act
ivat
ed by sever
aI 

al
so of
 cri
ti
caIi
m por
tance.Ast
rocyt
es and mi
crogl
ia  exogenous and endogenous l
igands such as LPS,
 

have not
 onl
y gener
all
y been 
viewed as 
cel
ls 
with 
the  heat
.shock pr
otei
ns,the 
ext
radom ai
n A 
of 
fibr
onect
in 

maj
or 
funct
ion 
of 
act
ivat
ion 
in 
response 
to 
cent
ri
fugaI
  and  amyl
oid.
  Compar
ed  wi
th  wi

d-ype  mi
t ce,
 
TLR4-
knockout
  and  poi
nt-
m ut
ant
  mi
ce  di
d  not
 
hyper
algesi
a ci
rcui
tr
y(as bel
ow)
.They ar
e al
so 

m munocompet
ent
 cel
ls and t
hus can respond I
ike  devel
op t
hermaI
  and m echani
caI
  al
lodyni
a af
ter
 


m mune cel
ls wi
thi
n t
he cent
raI
 ner
v ous syst
em .
  per
ipher
al ner
ve i
njur
y, t
oget
her
 wi
th  r
educed 
Mi
crogl
ia expr
ess t
he sam e sur
face mar
ker
s as  mi
crogl
iaI
  and  astr
ocyt
e  acti
vat
ion,
  remarkbl
y 

macr
ophages/monocyt
es.
  Subst
ant
iaI
  evi
dence  decr
eased expr
essi
on of
 int
erfer
on (
IFN)
,IL-
1,and 

ndi
cat
es t
hat
 it
 can cont
ribut
e t
o neur
opat
hic pai
n  TNF 

af
ter
 per
ipher
al 
ner
ve 
inj
ur
y.I
ndeed.when
 the 
gli
a i
s 
acti
vat
ed. a var
iet
y of
 chem i
caI
 subst
ances ar
e  Per
ipher
aIi
nfect
ion/
inf
lam mat
ion I
eads
 to act
ivat
ion
 

eleased t
o ampl
if
y pai
n m essage, t
hus causi
ng  of
 a br
ain-
to-spi
nal
 cor
d pat
hway,cul
minat
ing i
n the 
mor
e pai
nfuI
 hur
t.  Mi
crogl
ia ar
e acti
vated 
by 
event
s  creat
ion of
 hyper
algesi
a.Thi
s spi
nal
 ci
rcui
try al
so 

such as
 CNS i
niur
y,mi
crobi
aI
 invasi
on and some  cri
ti
cal
ly depends on t
he act
ivat
ion of
 spi
nal
 cor
d 
pai
n st
atus. whi
ch  I
eads to an i
ncrease i
n t
he  ast
rocyt
es and m i
crogl
ia. Anat
omi
cal
ly, astr
ocyt
es 
product
ion  of
  var
ious  i
nfl
am mat
ory   cyt
oki
nes,
  and m i
crogl
ia are cl
earl
y act
ivat
ed by per
ipher
al 
chem oki
nes and ot
her
 subst
ances. M any of
 the  i
nfect
ion/
inf
lam mat
ion. as  evi
denced  i
m munohi
s- 
subst
ances 
that
 can 
be 
rel
eased 
fr0m 
ast
rocyt
es 
and  t
ochemi
cal
ly by i
ncr
eased expr
essi
on of
 gl
ia-
speci
ic 

mi
crogl
ia  ar
e  know n  t
o  be  key  medi
ator
s  of
  act
ivat
ion mar
ker
s.  The r
eleased cyt
oki
nes f
TNF 
hyper
algesi
a,i
ncl
udi
ng NO ,exci
tat
ory ami
no aci
ds  and I
L.61
 m i
ght
 be j
nvol
ved j
n mi
crogl

al act
ivat
ion.
 

© Chinese Medical Association Publishing House


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Chi
nese
 Medi
cal
 Jour
nal
 2006;11
  11)
:930—
938  935 


L-1
 coul
d act
ivat
e m i
crogl
ia,whi
ch coul
d,i
n t
urn,
  I
argel
y  unmet
  t
her
apeut
ic  need. The  curr
ent
 
rel
ease prOnOci
cepti
ve com pounds and/
or di
rectl
y  phar
m acol
ogi
caI
 m ai
nst
ays of
 cl
ini
caI
 managem ent
 

nfl
uence  pai
n  pat
hways. The  r
ecr
uit
ment
  of
  f
Or neur
opathi
c pai
n ar
e t
ricycl
ic ant
i-depressant
s 
mi
crogl
ia i
s com monl
y associ
ated wi
th t
he act
ivat
ion  and cer
tai
n ant
i-convul
sant
s. ’
  But
 these drugs 

phosphor
ylat
ion1
  of
  p38  MAP  ki
nase.
  onl
y achi
eve 
cli
nical

y si
gni
fi
cant(
great
er 
than
 50%)
 
Phosphor
ylat
ion of
 p38 i
s pr
obabl
y a key 
int
racel
lul
ar  pai
n r
eli
ef i
n I
ess t
han 50% of
 pat
ients and ar
e 
si
gnal
 in
 mi
crogl
ia, whi
ch  r
egul
ates pai
n-r
elat
ed  associ
ated  wi
th  sub-
opt
im al
  si
de-efect
  pr
ofi
les.
 
acti
ons. Hyper
algesi
a can  be bl
ocked by spi
naI
  O pi
oids ar
e st
il
I t
he dr
ugs of
 choi
ce al
though
 they 
adm i
nistr
ati
on of
 drugs 
that
 di
srupt
 gl
iaI
 funct
ion.
Jz’
  are gener
all
y consi
der
ed t
o be I
ess efect
ive i
n 
Peri
pher
aI cyt
oki
nes 
Iead 
to 
the 
producti
on of
 centr
aI  neur
opat
hic pai
n t
han i
n i
nfl
am mat
ory  pai
n. 
cyt
oki
nes.whi
ch wi
lI
 par
tici
pat
e i
n t
he medi
ati
on of
 
cent
raI
 component
s of
 si
ckness.
  Fur
ther
 el
uci
dat
ion of
 the m echani
sms under
lyi
ng 
pai
n wi
ll
 assi
st i
n devel
opi
ng novel
 tar
get
s f
or dr
ug 
Sever
aI st
udi
es have shown t
hat
 speci
fi
c mi
crogl
ia  t
her
apy.Dr
ugs t
hat
 tar
get
 the gl

a and i
ts r
eleased 
and astr
c yt
o e i
nhi
bit
ors and/
or modul
ator
s can bl
ock  chem i
caI
 subst
ances ar
e pr
edi
cted t
o be power
fuI
 
and/
or  rever
se  neur
opathi
c  st
atus. The  m ost
  remedi
es f
or pai
n pr
obl
ems. And f
or neur
opat
hic 
com monl
y used com pounds ar
e fl
uor
c i
o trat
e and  pai
n,event
ual
ly,i
t m ay be possi
ble t
o i
m prove t
he 
mi
noc ycl
ine. Pr
evi
ous studi
es  have  shown  that
  qual
it
y of
 cl
ini
caI
 m anagement
 pr
otocol
s so t
hat
 
pr
e-em pt
ive  and  cur
ati
ve  f
luor
oci
trat
e  tr
eatment
  t
her
e  wi
lI
  be  a  move  away  f
rOm  the  curr
ent
 

sel
ect
ivel
y  bl
ocks  ast
rc yt
o e  and  mi
crogl
ia  di
sease-based  t
reat
ment
 towar
ds  sym pt
om s  or
, 
met
abol

sm) i
nhi
bit
s neur
opat
hic pai
n,  wher
eas
  ul
timat
ely,m echani
sm -
based 
ther
api
es.
 

mi
no
c ycl
ine(
a speci
fi
c mi
crogl

aI 
inhi
bit
or)bl
ocks 
the 
devel
opment
  of
  neuropathi
c  pai
n  but
  does not
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ivat
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ivat
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mechani
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indi
cat
e t
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m pl

cat
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ain  comm uni
cat
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mi
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 be 
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ty W B,Mar
chand E l
mmune and 

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vat
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orm a posi
tive  gl
ial
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Chi
n Med 
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mechani
sm  i
n  cannabi
noi
d-m edi
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tenuat
ion  of
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egul
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n t
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ivi
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