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CMJ 0366-6999 119 11 p930 01 PDF
CMJ 0366-6999 119 11 p930 01 PDF
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
i
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
s
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
I
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
t
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.
t
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
I
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
r
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
l
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
l
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).
i
m m une cel
l
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
1
2
found
t
hat
mast
cel
ls wer
e acti
vated i
n mo
d eI
of
par
tiaI
I
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
t
is contr
ibute to i
nnat
e i
m mune r
esponses.Moal
em et
i
m por
tant
to under
stand t
he under
lyi
ng pat
hophy-
aI
char
act
eri
zed
T-cel
Ii
nfi
l
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
I
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
I
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
i
nfect
ion and i
njur
y,i
ncl
udi
ng exposur
e t
o mi
crobi
al
cel
1 wal
I
fragment
s or
toxi
ns.i
rri
tant
chemi
cal
s and Some i
nvest
igat
ors1
5,1
6 bel
i
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
i
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
r
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
r
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
l
repl
i
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)
i
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.
i
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
t
he
hyper
algesi
c act
ion
seems
to
depend,i
n par
t,on i
m mune
cel
l
s ar
e l
arge
prot
eins
and
unl
ikel
y t
o cr
oss
neutr
ophi
l
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
r
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
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
l
s, and (
2)subdi
aphr
agmat
ic vagot
omy bl
ocks pr
oject
to
dis
tant
t
arget
regi
ons
al
t
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)
i
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
f
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
l
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
i
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
t
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
r
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
t
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
i
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
t
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
r
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
r
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
l
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
i
ncl
ude (
1) act
ive t
ranspor
t; (
2) cr
ossi
ng at
,
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
t
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
i
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
r
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)
t
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
i
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
i
ncr
eases
the
exci
tabi
l
iy
t of
dor
saI
hor
n neu
r
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
i
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
i
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
i
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
i
t
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 -
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
i
n the devel
opment
of
pai
n。 ’
。。 and i
t i
s wel
I
mi
crogl
ia i
n t
he
whi
te m ater
of
the spi
nal
cor
d t
hat
r
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
I
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
I
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,
t
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
t
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
l
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
i
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
i
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
i
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
r
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
f
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
i
al act
ivat
ion.
I
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
i
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
l
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
i
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
i
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
i
aI
inhi
bit
or)bl
ocks
the
devel
opment
of
neuropathi
c pai
n but
does not
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