Neuroscience Letters

Neuroscience Letters 361 (2004) 258-261

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Mini-review
cu!uncture an" en"or!#ins
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%i-&#en' (an)
Neuroscience *esearc# +nstitute, -e.in' /niversit0 an" 1e0
La2orator0 o3 Neuroscience (-e.in' /niversit0), Ministr0 o3
4"ucation, 38 5ue-6uan *oa",
7ei8in' 100083, -* 9#ina
4L&4:+4*
2stract
cu!uncture an" electroacu!uncture (4) as com!lementar0 an"
alternative me"icine #ave 2een acce!te" worl"wi"e mainl0 3or
t#e treatment o3 acute an" c#ronic !ain. &tu"ies on t#e
mec#anisms o3 action #ave reveale" t#at en"o'enous o!ioi"
!e!ti"es in t#e central nervous s0stem !la0 an essential role
in me"iatin' t#e anal'esic e33ect o3 4. ;urt#er stu"ies #ave
s#own t#at "i33erent .in"s o3 neuro!e!ti"es are release" 20 4
wit# "i33erent 3re$uencies. ;or e<am!le, 4 o3 2 (=
accelerates t#e release o3 en.e!#alin, (2-en"or!#in an"
en"omor!#in, w#ile t#at o3 100 (= selectivel0 increases t#e
release o3 "0nor!#in. com2ination o3 t#e two 3re$uencies
!ro"uces a simultaneous release o3 all 3our o!ioi" !e!ti"es,
resultin' in a ma<imal t#era!eutic e33ect. >#is 3in"in' #as
2een veri3ie" in clinical stu"ies in !atients wit# various
.in"s o3 c#ronic !ain inclu"in' low 2ac. !ain an" "ia2etic
neuro!at#ic !ain.
? 2003 4lsevier +relan" Lt". ll ri'#ts reserve".
1e0wor"s@ cu!unctureA 4lectroacu!unctureA B!ioi" !e!ti"esA
-ainA nal'esia
&cienti3ic stu"ies usin' mo"ern tec#nolo'0 on acu!uncture in
9#ina 2e'an in t#e late 1C50s w#en acu!uncture was 3oun" to 2e
a2le to success3ull0 ameliorate !ain !ro"uce" 20 sur'ical
!roce"ures. n interestin' 3in"in' was t#at mani!ulation o3 a
nee"le in t#e acu!oint o3 t#e volunteers !ro"uce" a slow
increase o3 t#e s.in !ain t#res#ol", reac#in' t#e !ea. in 30
min, 3ollowe" 20 an e<!onential "eca0 a3ter t#e removal o3 t#e
nee"le D24E. >#e involvement o3 some c#emical me"iators was
su''este". >#is #0!ot#esis was vali"ate" 20 a 9&; cross-
in3usion stu"0 in w#ic# t#e cere2roventricular 3lui" o2taine"
3rom t#e "onor ra22it su28ecte" to acu!uncture stimulation was
in3use" to t#e t#ir" ventricle o3 a naive reci!ient ra22it.
trans3erence o3 t#e anal'esic e33ect 3rom t#e "onor to t#e
reci!ient ra22it was o2serve" D25E, a !#enomenon w#ic# ma0 2e
inter!rete" as c#emical me"iation o3 electroacu!uncture (4)
anal'esia. -rior to t#e "iscover0 o3 en"o'enous o!ioi"s, we
3ocuse" on various can"i"ate neurotransmitters inclu"in'
monoamines, an" 3oun" t#at serotonin (5-(>) was most im!ortant
amon' classical neurotransmitters 3or t#e me"iation o3
acu!uncture anal'esia D12E.
>#e "iscover0 o3 en"o'enous o!ioi" !e!ti"es en#ance" t#e
stu"0 o3 t#e mec#anisms o3 acu!uncture-in"uce" anal'esia. >#e
o!ioi" rece!tor anta'onist nalo<one was use" as a
!#armacolo'ical tool 3or t#e stu"0 o3 t#e mec#anisms o3 4.
Ma0er et al. D21E an" -omeran= an" 9#iu D23E were amon' t#e
+n #onor o3 Man3re" FimmermannGs H0t# 2irt#"a0.
) >el.@ I 86-10-828010C8A 3a<@ I 86-10-820H220H.
4-mail a""ress@ #an8is#en'J28mu.e"u.cn (%.&. (an).
3irst to s#ow t#at acu!uncture-in"uce" anal'esia can 2e
2loc.e" 20 nalo<one 2ot# in #umans an" in mice, su''estin' t#e
!artici!ation o3 en"o'enous o!ioi"s. ;urt#er stu"ies D2E
reveale" t#at nalo<one can onl0 2loc. t#e anal'esic e33ect
in"uce" 20 4 o3 low 3re$uenc0 (4 (=), 2ut not t#at o3 #i'#
3re$uenc0 (200 (=), su''estin' t#at low- rat#er t#an #i'#-
3re$uenc0 stimulation tri''ers t#e release o3 o!ioi" !e!ti"es.
>#is was in "irect contrast wit# t#e #0!ot#esis summari=e" 20
(o.3elt in 1CC1 D1CE t#at central neuro!e!ti"es can 2e
release" onl0 20 #i'#-3re$uenc0 2ut not low-3re$uenc0
stimulation.
>#e "iscover0 o3 en.e!#alin in 1CH5 was soon 3ollowe" 20
t#at o3 !-en"or!#in in 1CH6 an" "0nor!#in in 1CHC. >#ere was a
lon' la!se 2e3ore t#e "iscover0 o3 t#e 3ourt# en"o'enous
o!ioi" !e!ti"e, t#e en"omor!#in, in 1CCH. K#ile t#e
en"omor!#in was consi"ere" as t#e !ure m o!ioi" rece!tor
a'onist D2HE an" "0nor!#in t#e relativel0 !ure 1 o!ioi"
a'onist D3E, t#e en.e!#alin an" !-en"or!#in were mi<e" m an" "
o!ioi" rece!tor a'onists. 7ase" on "i33erences in t#e +950 o3
nalo<one towar" "i33erent t0!es o3 o!ioi" rece!tors we 3oun"
t#at 2ot# low- an" #i'#- 3re$uenc0 4 anal'esia were nalo<one
reversi2leA t#e .e0 3actor was t#e "osa'e. >#us, t#e +L50 o3
nalo<one 3or 2loc.a"e o3 t#e anal'esic e33ect !ro"uce" 20 2,
15 an" 100 (= 4 anal'esia was 3oun" to 2e 0.5, 1.0 an" 20
m'/.', res!ectivel0 D14E. >#is result su''ests t#at t#e
anal'esia in"uce" 20 2 (= 4 was me"iate" 20 t#e m rece!tor
an" t#at o3 100 (= 4 20 1 o!ioi" rece!tors. >#is conclusion
was veri3ie" later 20 t#e use o3 su2t0!e s!eci3ic o!ioi"
rece!tor anta'onists D5E. >#e "irect evi"ence was o2taine"
0304-3C40/03/M - see 3ront matter ? 2003 4lsevier +relan" Lt".
ll ri'#ts reserve". "oi@10.1016/8.neulet.2003.12.01C
%.-&. (an / Neuroscience Letters 361 (2004) 258-261
25C
N 2e3ore O 3ter 4
9ontrol 2(= 15(= 100(=
20 measurin' t#e neuro!e!ti"e release in t#e central nervous
s0stem tri''ere" 20 4 o3 "i33erent 3re$uencies. *ats were
'iven 4 at 2, 15 or 100 (=, usin' ra"iant #eat-in"uce" tail
3lic. latenc0 (>;L) as t#e en"!oint o3 nocice!tion. -er3usion
o3 t#e su2arac#noi" s!ace o3 t#e s!inal cor" was !er3orme" an"
t#e !er3usate was collecte" in 30 min intervals 2e3ore or
"urin' t#e 4 stimulation. *a"ioimmunoassa0 was use" to
measure t#e contents o3 met-en.e!#alin an" "0nor!#in an" 7
D8E. *esults s#own in ;i'. 1 s#ow t#at 2 (= 4 !ro"uce" a H
3ol" increase in met-en.e!#alin 2ut not "0nor!#in . +n
contrast, 100 (= 4 !ro"uce" a 2 3ol" increase in t#e release
o3 "0nor!#in 2ut not met- en.e!#alin. !arallel c#an'e was
reveale" 3or 2ot# "0nor!#in an" "0nor!#in 7 immunoreactivit0
("ata not s#own). 4 o3 15 (= !ro"uce" a !artial activation o3
2ot# en.e!#alins an" "0nor!#ins. No increase in en"o'enous
o!ioi" release was o2serve" in non-res!on"er rats t#at "i" not
s#ow an0 increase in >;L a3ter 4 stimulation D8E.
;urt#er stu"ies #ave s#own t#at !-en"or!#in D18E an"
en"omor!#in D1HE s#are similar c#aracteristics o3 a
stimulation-in"uce" release !ro3ile as en.e!#alin, i.e.
!re3era2le to 2 (= stimulation, leavin' "0nor!#in as t#e onl0
o!ioi" !e!ti"e res!onsive to #i'#-3re$uenc0 stimulation
D15,16E. K#ile t#ere was a 'eneral consensus t#at m an" "
o!ioi" rece!tor a'onists !ossess an anal'esic e33ect,
controvers0 remains on w#et#er "0nor!#in is anal'esic D15, 22E
or #0!eral'esic D1,20E. 9#av.in et al. re!orte" t#at "0nor!#in
s#owe" a ver0 !otent o!ioi" e33ect on 'uinea !i' ileum assa0,
2ut was not anal'esic w#en in8ecte" into t#e 2rain D3E. (an
D15E an" -ierse0 D22E were t#e 3irst to s#ow t#at "0nor!#in is
anal'esic w#en in8ecte" intrat#ecall0 into t#e su2arac#noi"
s!ace o3 t#e s!inal cor" o3 rats or mice. >#e0 also warne"
t#at "0nor!#in #as a !aral0tic e33ect at #i'#er "oses. 9are
s#oul" 2e ta.en to "i33erentiate t#e nalo<one-resistant, non-
o!ioi" !aral0tic e33ect 3rom t#e nalo<one-reversi2le anal'esic
e33ect. >#ere3ore, it is critical to see w#et#er anal'esia can
2e !ro"uce" 20 acceleratin' t#e !ro"uction an" release o3 t#e
en"o'enous "0nor!#in D13,
16E. 9#en' et al. D6E re!orte" t#at "0nor!#in s0nt#esis is
un"er t#e control o3 a P"own stream re'ulator0 element wit#
anta'onistic mo"ulationQ (L*4M), a transcri!tional re!ressor
actin' constitutivel0 to su!!ress !ro"0nor!#ine 'ene
e<!ression. 1noc.in' out L*4M increases "0nor- !#in
e<!ression, resultin' in a !ro3oun" re"uction in !ain 2e#avior
in animal mo"els o3 acute, in3lammator0 an" neuro!at#ic !ain
DHE. >#is 'ives stron' su!!ort to t#e #0!ot#esis t#at
en"o'enousl0 release" "0nor!#in is in"ee" anal'esic rat#er
t#an #0!eral'esic or !aral0tic (;i'. 2).
;rom ;i'. 2 it is o2vious t#at a s#ar! "emarcation seems to
e<ist 2etween t#e 2 (= si"e an" t#e 100 (= si"e. +n a c#art
wit# a lo' scale, 15 (= is in t#e mi""le !oint 2etween 2 an"
100 (=, w#ic# can !artiall0 activate 2ot# si"es. +n or"er to
ma<imi=e t#e anal'esic e33ect, 4 wit# alternatin' 2 an" 100
(= ("ense an" "is!erse, LL) mo"e o3 action is use". >#us, t#e
two electro"es o3 stimulation can 2e a!!lie" on two acu!oints
transcutaneousl0 or !ercutaneousl0 an" connecte" to a !ulse
'enerator w#ic# emits s$uare waves o3 2 (= 3or 3 s an" t#en
automaticall0 s#i3ts to 100 (= 3or 3 s. >#e anal'esic e33ect
in"uce" 20 t#is LL mo"e o3 stimulation was 3oun" to 2e
si'ni3icantl0 more e33ective t#an t#e !ure low- or !ure #i'#-
3re$uenc0 stimulation D4E. >#is conce!t o3 simulation !attern
is now acce!te" 20 clinicians an" is wi"el0 use" in most 4
"evices.
$uestion arises t#at i3 t#e 2rain can !erceive alternative
2 an" 100 (= (2/100) electrical stimulation 3or t#e
"i33erential release o3 en.e!#alin an" "0nor!#in,
res!ectivel0, coul" we use 2 (= stimulation on one #an" an"
100 (= on t#e ot#er #an" (2 I 100) simultaneousl0 an"
continuousl0, so t#at en.e!#alin an" "0nor!#in can 2e release"
simultaneousl0 in a 3ull e<tentR >#is was teste" in a rat
e<!eriment. >wo !ossi2ilities e<iste". Bne is t#at t#e 2rain
can "i33erentiate t#e two 3re$uencies clearl0 an" se!aratel0,
so t#at 2ot# en.e!#alin an" "0nor!#in are release"
simultaneousl0. >#e ot#er is t#at si'nals 3rom t#e two sites
o3 stimulation are mer'e" in t#e reticular 3ormation so t#at
t#e0 are !erceive" as 102 (=, w#ic# is almost
in"istin'uis#a2le 3rom 100 (=. s a result, onl0 "0nor!#in
will 2e release". &ince it #as 2een !rove" t#at 2 (=
o o o o o o o o 3 2 1 0 3 2 1 o o."o."" " " "
3Sesn)ta)" le.4"s.4%i-.4$"louT
oooooooooooo
+$.0.5.0l$.08cUlU.0.5c2 0i2.1.lc5c53VicVi11cic5
WLSesnt@aV" Xeui"s uY %i-uZell"C0luLi%
;i'. +. >#e e33ect o3 4 o3 "i33erent 3re$uencies on t#e
content o3 ir-
en.e!#alin an" ir-"0nor!#in in t#e s!inal !er3usate o3
res!on"er an" non- ;i'. 2. &c#ematic "ia'ram s#owin' t#e
o!ioi" mec#anisms o3 4-in"uce" res!on"er rats D8E.
anal'esia.
260
%.-&. (an / Neuroscience Letters 361 (2004) 258-261
;i'. 3. com2ination o3 electrical stimulation o3 "i33erent
3re$uencies ma0 !ro"uce "i33erent !ro3iles o3 neuro!e!ti"e
release. P2/100 (=Q stan"s 3or an alternative mo"e o3
stimulation w#ere 2 (= is alternatin' wit# 100 (=, eac#
lastin' 3or 3 s. P2 I 100 (=Q is a mo"e o3 stimulation w#ere 2
(= stimulation is a!!lie" on t#e le3t #in"le' an" 100 (= on
t#e ri'#t #in"le'. -er3usate 3rom t#e s!inal su2arac#noi"
s!ace was use" 3or ra"ioimmunoassa0 o3 met-en.e!#alin an"
"0nor!#in D26E.
4 can activate en.e!#alin, !-en"or!#in an" en"omor!#in
simultaneousl0, we use" en"omor!#in as a re!resentative mar.er
in t#e !resent stu"0. &ome o3 t#e results are "e!icte" in ;i'.
3. s was !re"icte", 2/100 (= stimulation increase" t#e
release o3 2ot# "0nor!#in an" en"omor!#in, w#ereas 2 I 100 (=
stimulation increase" t#e release o3 onl0 "0nor!#in, 2ut not
en"omor!#in. +n ot#er wor"s, 2 I 100 stimulation "oes not seem
to carr0 t#e !ure 2 (= in3ormation D26E. +t is t#us o2vious
t#at a !ro!er com2ination o3 "i33erent 3re$uencies ma0 !ro"uce
a ma<imal release o3 a coc.tail o3 neuro!e!ti"es 3or 2etter
t#era!eutic e33ects.
>#e 3in"in's o2taine" 3rom e<!erimental animals nee" to 2e
con3irme" in #umans in clinical !ractice. K#ite an" #is
collea'ues at t#e /niversit0 o3 >e<as &out#western Me"ical
9enter o3 t#e /nite" &tates #ave !er3orme" a series o3 stu"ies
to assess w#et#er electrical stimulation o3 t#e alternative
mo"e woul" !ro"uce a si'ni3icantl0 stron'er anal'esic e33ect
t#an t#at !ro"uce" 20 stimulation o3 3i<e" 3re$uenc0. >a.in'
t#e re"uction o3 t#e !ost-o!erative re$uirement o3 o!iate
"osa'e as an in"e< 3or anal'esia, t#e0 #ave reveale" t#at t#e
alternative mo"e stimulation re"uce" t#e mor!#ine re$uirement
20 53[, w#ereas a constant low (2 (=) or constant #i'# (100
(=) 3re$uenc0 !ro"uce" onl0 a 32[ or 35[ "ecrease,
res!ectivel0 D10E. &imilar results were o2taine" in clinical
stu"ies on low 2ac. !ain DCE an" "ia2etic neuro!at#ic !ain
D11E.
+n conclusion, stu"0 on t#e mec#anisms o3 acu!uncture
e33ects #as le" to a ma8or 3in"in' in neuroscience t#at
neuro!e!ti"es in 9N& can 2e mo2ili=e" 20 electrical
stimulation o3 "i33erent 3re$uencies a!!lie" at !eri!#eral
sites. Letails o3 t#e inter3ace 2etween electrical co"in' an"
c#emical co"in' an" t#e !otential clinical a!!lication o3
t#ese 3in"in's "eserve 3urt#er investi'ation.
c.nowle"'ements
>#is stu"0 was su!!orte" 20 t#e National 7asic *esearc#
-ro'ram (\1CCC054000) an" National Natural &cience ;oun"ation
(303 30026) o3 9#ina an" N+L (L 03C83), N+(, /&.
*e3erences
D1E *.M. 9au"le, .%. Mannes, L0nor!#in@ 3rien" or 3oeR, -ain
8H (2000) 235-23C.
D2E *. 9#an', 7. -omeran=, 4lectroacu!uncture anal'esia coul"
2e me"iate" 20 at least two !ain-relievin' mec#anisms@
en"or!#in an" non-en"or!#in s0stems, Li3e &ci. 25 (1CHC)
1C5H-1C62.
D3E 9. 9#av.in, L.;. %ames, . \ol"stein, L0nor!#in is a
s!eci3ic en"o'enous le'en" o3 t#e 1-o!ioi" rece!tor, &cience
215 (1C82) 413-415.
D4E 5.(. 9#en, &.;. \uo, 9.\. 9#an', %.&. (an, B!timal
con"itions 3or elicitin' ma<imal electroacu!uncture
anal'esia wit# "ense an" "is!erse mo"e stimulation, m. %.
cu!unct. 22 (1CC4) 4H-53.
D5E 5.(. 9#en, %.&. (an, ll t#ree t0!es o3 o!ioi" rece!tors
in t#e s!inal cor" are im!ortant 3or 2/15 (=
electroacu!uncture anal'esia, 4ur. %. -#armacol. 211 (1CC2)
203-210.
D6E (.6.M. 9#en', \.M. -itc#er, &.*. Laviolette, +.T.
K#is#aw, 1.+. >on', L.1. 1oc#erit=, >. Ka"a, N.. %o=a, M.
9rac.ower, %. \oncalves, +. &arosi, %.*. Koo"'ette, .%.
Bliveira-"os-&antos, M. +.ura, L. van "er 1oo0, M.K. &alter,
%.M. -ennin'er, L*4M is a critical transcri!tional
re!ressor 3or !ain mo"ulation, 9ell 108 (2002) 31-43.
DHE M. 9osti'an, 9.%. Kool3, No L*4M, no !ain. 9losin' t#e
s!inal 'ate, 9ell 108 (2002) 2CH-300.
D8E (. ;ei, \.5. 5ie, %.&. (an, Low an" #i'# 3re$uenc0
electroacu!uncture stimulation release met-en.e!#alin an"
"0nor!#in in rat s!inal cor", &ci. 7ull. 9#ina 32 (1C8H)
14C6-1501.
DCE 4.. \#oname, K.;. 9rai', -.;. K#ite, (.4. #me", M..
(am=a, 7.N. (en"erson, N.M. \a8ra8, -.%. (u2er, *.%.
\atc#el, -ercutaneous electrical nerve stimulation 3or low
2ac. !ain@ a ran"omi=e" crossover stu"0, %. m. Me". ssoc.
281 (1CCC) 818-823.
D10E M.. (am=a, -.;. K#ite, (.4. #me", 4.. \#oname, 433ect
o3 t#e 3re$uenc0 o3 transcutaneous electrical nerve
stimulation on t#e !osto!erative o!ioi" anal'esic
re$uirement an" recover0 !ro3ile, nest#esiolo'0 C1 (1CCC)
1232-1238.
D11E M.. (am=a, -.;. K#ite, K.;. 9rai', 4.&. \#oname, (.4.
#me", >.%. -roctor, 9.4. Noe, .&. :a.#aria, N. \a8ra8,
-ercutaneous electrical nerve stimulation@ a novel anal'esic
t#era!0 3or "ia2etic neuro!at#ic !ain, Lia2et. 9are 23
(2000) 365-3H0.
D12E %.&. (an, -.(. 9#ou, 9.(. Lu, >.(. 6an', L.(. Lu, M.;.
*en, >#e role o3 central 5-(> in acu!uncture anal'esia, &ci.
&in. 22 (1CHC) C1-104.
D13E %.&. (an, 5.(. 9#en, &.L. &un, 5.%. 5u, 6. 6uan, &.9.
6an', %.5. (an, L. >erenius, 433ect o3 low- an" #i'#-
3re$uenc0 >4N& on met- en.e!#alin-r'--#e an" "0nor!#in
immunoreactivit0 in #uman lum2ar 9&;, -ain 4H (1CC1) 2C5-
2C8.
D14E %.&. (an, 5.F. Lin', &.\. ;an, >#e 3re$uenc0 as t#e
car"inal "eterminant 3or electroacu!uncture anal'esia to 2e
reverse" 20 o!ioi" anta'onists, cta -#0siol. &in. 38 (1C86)
4H5-482.
D15E %.&. (an, 9.K. 5ie, L0nor!#in@ !otent anal'esic e33ect in
s!inal cor" o3 t#e rat, Li3e &ci. 31 (1C82) 1H81-1H84.
D16E %.&. (an, \.5. 5ie, L0nor!#in@ im!ortant me"iator 3or
electroacu!uncture anal'esia in t#e s!inal cor" o3 t#e
ra22it, -ain 18 (1C84) 36H-3H6.
D1HE F. (an, 6.(. %ian', 6. Kan, 6. Kan', %.1. 9#an', %.&.
(an, 4n"omor!#in-1 me"iates 2 (= 2ut not 100 (=
electroacu!uncture anal'esia in t#e rat, Neurosci. Lett. 2H4
(1CCC) H5-H8.
D18E 9.M. (e, %.&. (an, ttenuation o3 low rat#er t#an #i'#
3re$uenc0 electroacu!uncture anal'esia 3ollowin'
microin8ection o3 !-en"or-
%.3 u="%B4B-/
>B
8
o o o o o
5 4 3 2 1
%.:.4ll"%B/o
(+4/6/) alensnte"
%.-&. (an /Neuroscience Letters 361 (2004) 258-261
261
!#in antiserum into t#e !eria$ue"uctal 'ra0 in rats, cu!unct.
&ci. +nt. %. 1 (1CC0) 1C-2H.
D1CE >. (o.3elt, Neuro!e!ti"es in !ers!ective@ t#e last ten
0ears, Neuron H (1CC1) 86H-8HC.
D20E >.M. Lau'#lin, .. Larson, \.L. Kilco<, Mec#anisms o3
in"uction o3 !ersistent nocice!tion 20 "0nor!#in, %.
-#armacol. 4<!. >#er. 2CC (2001) 6-11.
D21E L.%. Ma0er, L.L. -rice, . *a3ii, nta'onism o3
acu!uncture anal'esia in man 20 t#e narcotic anta'onist
nalo<one, 7rain *es. 121 (1CHH)368-3H2.
D22E M.;. -ierce0, 1. :arner, L.. &c#roe"er, nal'esic
activit0 o3 intras!inall0 a"ministere" "0nor!#in an"
et#0l.etoc0cla=ocine, 4ur. %. -#armacol. 80 (1C82) 283-284.
D23E 7. -omeran=, L. 9#iu, Nalo<one 2loc.s acu!uncture
anal'esia an"
causes #0!eral'esia@ en"or!#in is im!licate", Li3e &ci. 1C
(1CH6) 1H5H -1H62.
D24E *esearc# \rou! o3 cu!uncture nest#esia, -e.in' Me"ical
9olle'e, 433ect o3 acu!uncture on t#e !ain t#res#ol" o3
#uman s.in, Natl. Me". %. 9#ina 3 (1CH3) 151-15H.
D25E *esearc# \rou! o3 cu!uncture nest#esia, -e.in' Me"ical
9olle'e, >#e role o3 some neurotransmitters o3 2rain in
acu!uncture anal'esia, &ci. &in. 1H (1CH4) 112-130.
D26E 6. Kan', 6. F#an', K. Kan', 6. 9ao, %.&. (an, New
evi"ence 3or s0ner'istic anal'esia !ro"uce" 20 en"omor!#in
an" "0nor!#in, 9#in. %. -ain Me". 8 (2002) 118-11C.
D2HE %.4. Fa"ina, L. (ac.ler, L.%. \e, .%. 1astin, !otent
an" selective en"o'enous a'onist 3or t#e m-o!iate rece!tor,
Nature 386 (1CCH) 4CC-501.