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94 Revista Brasileira de AnestesiologiaVol. 57, No 1, Janeiro-Fevereiro, 2007

Rev Bras Anestesiol ARTIGO DE REVISO2007; 57: 1: 94-105 REVIEW ARTICLE

RESUMORocha APC, Kraychete DC,Lemonica L, Carvalho LR, Barros GAM,Garcia JBS, Sakata RK Dor: Aspectos Atuais da SensibilizaoPerifrica e Central.

JUSTIFICATIVA E OBJETIVOS:As pesquisas recentes tm foca-lizado a plasticidade bioqumica e estrutural do sistema nervoso

decorrente da leso tissular. Os mecanismos envolvidos na tran-

sio da dor aguda para crnica so complexos e envolvem a

interao de sistemas receptores e o fluxo de ons intracelulares,

sistemas de segundo mensageiro e novas conexes sinpticas. O

objetivo deste artigo foi discutir os novos mecanismos que envol-

vem a sensibilizao perifrica e central.

CONTEDO:A leso tissular provoca aumento na resposta dosnociceptores, chamada de sensibilizao ou facilitao. Esses fe-

nmenos iniciam-se aps a liberao local de mediadores infla-

matrios e a ativao de clulas do sistema imune ou de receptores

especficos no sistema nervoso perifrico e central.

CONCLUSES:As leses do tecido e dos neurnios resultam emsensibilizao de nociceptores e facilitao da conduo nervo-

sa central e perifrica.

Unitermos: DOR: mecanismos, sensibilizao perifrica, sen-sibilizao central.

SUMMARYRocha APC, Kraychete DC, Lemonica L, Carvalho LR, Barros GAM,Garcia JBS, Sakata RK Pain: Current Aspects on Peripheral andCentral Sensitization.

BACKGROUND AND OBJECTIVES:Current research has focusedon the biochemical and structural plasticity of the nervous system

secondary to tissue injury. The mechanisms involved in the tran-

sition from acute to chronic pain are complex and involve the

interaction of receptor systems and the flow of intracellular ions,

second messenger systems, and new synaptic connections. The

aim of this article was to discuss the new mechanisms concerning

peripheral and central sensitization.

CONTENTS:Tissue injury increases the response of nociceptors,known as sensitization or facilitation. These phenomena begin after

the local release of inflammatory mediators and the activation of the

cells of the immune system or specific receptors in the peripheral

and central nervous system.

CONCLUSIONS:Tissue and neuronal lesions result in sensitiza-tion of the nociceptors and facilitation of the central and peripheral

nervous conduction.

Key Words: PAIN: mechanisms, peripheral sensitization, centralsensitization.

INTRODUO

Apesar de a Associao Internacional para o Estudo daDor (IASP) ter definido a dor como uma sensao sub-jet iva relacionada com uma leso tissular, h evidnciasque essa associao possa no ocorrer. A cefalia e a dorplvica crnica, por exemplo, parecem existir sem leso tis-sular detectvel pelos mtodos diagnsticos disponveis naprtica clnica atual, favorecendo a hiptese de que pode haveralteraes neurofuncionais restritas ao mbito biomolecular,cuja interao pouco conhecida entre neuromediadores,neurotransmissores e transdutores de sinais, em uma rede

de bilhes de sinapses, o que dificulta a compreenso daetiologia da dor 1. Por outro lado, o trauma e a estimulaodo sistema nervoso perifrico ou central tambm podem al-terar as respostas imunes. Como conseqncia, observa-sea ativao de peptdeos e receptores, com posterior traduodo sinal para o meio intracelular. Nesse contexto, o avanono conhecimento da neuroanatomia das vias de conduo,da neurofarmacologia e da fisiopatologia da dor facilita odesenvolvimento de pesquisas visando a novas modalidadesde tratamento. Assim, a analgesia efetiva para as sndro-mes dolorosas ainda um grande desafio.

Dor: Aspectos Atuais da Sensibilizao Perifrica e Central*Pain: Current Aspects on Peripheral and Central Sensitization

Anita Perptua Carvalho Rocha1, Durval Campos Kraychete, TSA2,Lino Lemonica, TSA3, Ldia Raquel de Carvalho4,

Guilherme Antnio Moreira de Barros, TSA5, Joo Batista dos Santos Garcia, TSA6, Rioko Kimiko Sakata, TSA7

*Recebido do (Received from) CET/SBA da Faculdade de Medicina de Botu-catu da Universidade Estadual de So Paulo (FMB UNESP), Botucatu, SP

1. Mestre em Anestesiologia pela FMB UNESP; Coordenadora do Servio

de Dor Aguda do Hospital da Sagrada Famlia

2. Professor Doutor, Disciplina de Anestesiologia da UFBA; Coordenador do

Ambulatrio de Dor da UFBA

3. Professor Doutor do Departamento de Anestesiologia da FMB UNESP;

Responsvel pelo Servio de Terapia Antlgica e Cuidados Paliativos

4. Professor Doutor do Departamento de Bioestatstica do Instituto de

Biocincias, UNESP

5. Professor Doutor do Departamento de Anestesiologia da FMB UNESP

6. Professor Doutor da Disciplina de Anes tesiologia, Universidade Federal do

Maranho; Presidente do Comit de Dor da Sociedade Brasileira de

Anestesiologia7. Professor Doutor da Disciplina de Anestesiologia da Universidade Federal

de So Paulo. Coordenador do Setor DOR da UNIFESP

Apresentado (Submitted) em 12 de janeiro de 2006Aceito (Accepted) para publicao em 07 de setembro de 2006

Endereo para correspondncia (Correspondence to):Dra. Anita Perptua Carvalho Rocha

Rua Pacfico Pereira, 457/404

Garcia

40100170 - Salvador-BA

E-mail: [email protected]

Sociedade Brasileira de Anestesiologia, 2007


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Revista Brasileira de Anestesiologia 95Vol. 57, No 1, Janeiro-Fevereiro, 2007

No Brasil 2 e em outros pases 3,4, 10% a 50% dos indivdu-os procuram clnicas-gerais por causa da dor 5-8. A dor estpresente em mais de 70% dos pacientes que buscam osconsultrios brasileiros por motivos diversos, sendo a razode consultas mdicas em um tero dos casos. Esse argu-mento enfatiza a importncia da busca de elementos que

permitam uma melhor abordagem da dor aguda e crnica.O objetivo desta reviso foi discutir a fisiopatologia da dor,enfatizando os mecanismos perifricos e centrais da trans-misso dolorosa.

MECANISMOS PERIFRICOS DA DOR

O primeiro passo na seqncia dos eventos que originamo fenmeno doloroso a transformao dos estmulos agres-sivos em potenciais de ao que, das fibras nervosas peri-fricas, so transferidos para o sistema nervoso central 9.Os receptores especficos para a dor esto localizados nas

terminaes de fibras nervosas A e C

10,11

e, quando ati-vados, sofrem alteraes na sua membrana, permitindo adeflagrao de potenciais de ao.As terminaes nervosas das fibras nociceptivas A e C (no-ciceptores) so capazes de traduzir um estmulo agressivode natureza trmica, qumica ou mecnica, em estmulo el-trico que ser transmitido at o sistema nervoso central einterpretado no crtex cerebral como dor. As fibras A somielinizadas e as fibras C no so mielinizadas e possuema capacidade de transmitir estmulos dolorosos em diferen-tes velocidades. As fibras A, em funo da presena da bai-nha de mielina, transmitem o estmulo doloroso de formarpida, enquanto as fibras C so responsveis pela trans-

misso lenta da dor. Ambas so classificadas em subtiposA1, A2, C1 e C2 (Tabela I). O tipo de fibra nociceptiva pa-rece estar envolvido com alteraes perifricas distintas nas

diversas sndromes dolorosas, e poder, no futuro, contri-buir para o tratamento mais eficaz da dor.Os nociceptores, ento, so sensibilizados pela ao desubstncias qumicas, denominadas algiognicas, presentesno ambiente tissular 12: acetilcolina, bradicinina, histamina,serotonina, leucotrieno, substncia P, fator de ativao

plaquetrio, radicais cidos, ons potssio, prostaglandinas,tromboxana, interleucinas, fator de necrose tumoral (TNF),fator de crescimento nervoso (NGF) e monofosfato cclico deadenosina (AMPc) 13-15 (Figura 1).Quando o estmulo provoca a leso tecidual, h o desenca-deamento de processo inflamatrio seguido de reparao.As clulas lesadas liberam enzimas de seu interior, que noambiente extracelular degradam cidos graxos de cadeialonga e atuam sobre os cininognios, dando origem for-mao de cininas. As cininas so pequenos polipeptdeosda

2-calicrena presente no plasma ou nos lquidos org-

nicos. A calicrena uma enzima proteoltica que ativada

pela inflamao e outros efeitos qumicos ou fsicos sobreo sangue ou os tecidos. Ao ser ativada, a calicrena atuaimediatamente sobre a 2-globulina, liberando a cinina de-nominada calidina, que , assim, convertida em bradicininapor enzimas teciduais. Uma vez formada, a bradicinina pro-voca intensa dilatao arteriolar e aumento da permea-bilidade capilar, contribuindo para a propagao da reaoinflamatria 16.Tambm, a ao da fosfolipase A na membrana celular pro-voca a liberao de cido araquidnico. Este metabolizadopor trs sistemas enzimticos principais: a cicloxigenase,de cuja atuao obtm-se as prostaglandinas, os trom-boxanos e as prostaciclinas; a lipoxigenase, que provoca a

produo de leucotrienos e lipoxinas; e o citocromo P-450,que origina os denominados produtos da via da epoxige-

Tabela I Subtipos das Fibras Nervosas A e C

Tipo de Fibra Caractersticas

Fibras A tipo I Respondem a tem peratura em torno de52C, so insensveis a capsaicina epossuem resposta mediada pelosreceptores VRL-1

Fibras A tipo II So sensveis a temperatura em torno de

43C, a capsaicina e ativam, via receptoresVR1, canais catinicos no-seletivospermeveis ao clcio

Fibras C tipo I Contm substncia P e CGRP e expressamreceptores tirocinase A, para o fator decrescimento nervoso. So responsivas acapsaicina e a prtons

Fibras C tipo II Expressam receptores purinrgicos P2X3

para adenosina e um grupo de carboidratosde superfcie, a -D-galactose, capaz dese ligar a lecitina IB-4, sensveisseletivamente a prtons

Membranacelular

Bradicinina

Leso

Acetilcolina

HistaminaEnzimasH+

TNF-K+

Substncia PSerotonina

ProstaglandinasSubstnciasalgiognicas

Figura 1 Liberao de Substncias Algiognicas aps a LesoTecidual

DOR: ASPECTOS ATUAIS DA SENSIBILIZAO PERIFRICA E CENTRAL


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nase. Essas substncias, sobretudo as prostaglandinas E2

(PGE2), promovem diminuio do limiar de excitabilidadedos nociceptores 17.Do mesmo modo, clulas inflamatrias, macrfagos e leu-ccitos liberam citocinas que vo contribuir para a migraode novas clulas para o local da leso. H produo e libe-

rao de interleucina-1 e 6, fator de necrose tumoral, selec-tina, fatores quimiotticos, xido ntrico e substnciasoxidantes. Novos receptores, ento, so recrutados e pas-sam a fazer parte do processo inflamatrio. A substncia Pe a neurocinina A produzem vasodilatao e aumento dapermeabilidade vascular, contribuindo tambm para a ma-nuteno do processo inflamatrio 18.A bradicinina, a prostaglandina E2, o fator de crescimento ner-voso (NGF) e as interleucinas, contudo, parecem exercer pa-pel fundamental na nocicepo perifrica. A prostaglandinae a bradicinina causam alteraes em receptores especfi-cos (TRPV1) acoplados a canais inicos ligante-dependentevia ativao do AMPc, e das protenas cinases A (PKA) e C(PKC), reduzindo o tempo ps-hiperpolarizao da membra-na neural, causando reduo do limiar para disparo da fibranervosa.As neurotrofinas aumentam a sntese, o transporte axonalantergrado e quantidade de SP e CGRP nas fibras C tipo 1e reduzem a atividade do cido gama-aminobutrico (GABA),tanto nas terminaes nervosas perifricas quanto nas cen-trais. Ao lado disso, provocam mudanas nos receptoresvanilides (VR1) de fibras A acoplados a canais inicos ligan-te-dependente e acionam as protenas cinases ativadas pormitgenos (MAPK) que podem fosforilar o AMPc e iniciar atranscrio gentica responsvel por alteraes fenotpicas, as

quais contribuem para a amplificao da eficcia sinptica.A persistncia da agresso causa modificaes no sistemanervoso perifrico e sensibilizao de fibras nervosas, comconseqente hiperalgesia e aumento dos nveis de AMPc eclcio nos nociceptores. Esse fenmeno ocorre por aodos mediadores inflamatrios e conseqente atividade es-pontnea dos neurnios, aumento da resposta a estmulossupraliminares e diminuio do limiar de ativao dos noci-ceptores 18-20. Um tipo particular de nociceptor referidocomo nociceptor silente, o qual ativado aps inflamaoou depois de ter ocorrido leso tissular. As estimativas sode que 40% das fibras C e 30% das fibras A contribuemcom nociceptores silentes. Aps a liberao dos produtosqumicos da leso, esses receptores previamente silencio-sos so ativados por estmulos trmicos e mecnicos e de-senvolvem descargas espontneas, tornando-se capazesde responder de maneira intensa a estmulos nociceptivose no-nociceptivos 21-22 (Figura 2).Em resumo, a agresso tecidual resulta na acumulao demetablitos do cido araquidnico. A produo de prosta-glandinas e de leucotrienos leva a degranulao de mas-tcitos e a ativao direta de fibras nervosas, macrfagos elinfcitos. H liberao de mediadores, como potssio,serotonina, substncia P, histamina e cininas. Ocorrem al-

teraes na permeabilidade vascular, no fluxo sangneolocal e produo dos sinais clssicos inflamatrios de ru-bor, calor, dor, tumor e impotncia funcional. Tem incio o pro-cesso de sensibilizao perifrica com conseqenteexacerbao da resposta ao estmulo doloroso 20-22.Os neuromediadores perifricos levam a despolarizao damembrana neural por tempo prolongado, com conseqenteaumento da condutividade dos canais de sdio e clcio e re-duo do influxo de potssio e cloro para o meio intracelular.

Os canais de sdio esto envolvidos na gnese da hiperex-citabilidade neuronal e podem estar e podem ser classifi-cados em dois grandes grupos: os sensveis tetrodotoxina(TTXs), que esto presentes nas fibras A, em todo sistemanervoso e no gnglio da raiz dorsal; e os resistentes tetro-dotoxina (TTXr), que so encontrados especialmente nas fi-bras C do gnglio da raiz dorsal 23.Apesar de a leso perifrica da fibra nervosa tipo C provo-car reduo no corno dorsal da medula espinhal de SP, deneurotrofinas (BDNF), de receptores (VR1 e P2X3), de canaisde clcio tipo N de alta voltagem, h regulao ascendentede canais TTXs tipo III e existe a translocao do corpo ce-lular para o neuroma de canais de sdio (TTXr), facilitandoo aumento da excitabilidade nervosa 24. O exposto aconte-ce caso a fibra nervosa esteja intacta (inflamao), ou seja,existe um aumento de neuromediadores excitatrios no cor-no dorsal da medula espinhal e uma maior expresso decanais de sdio (TTXr), fato que facilita a hiperexcitabilidadeneuronal e dificulta a resposta ao tratamento com anest-sicos locais 24.Tambm pode haver em ambas as situaes descritas, so-bretudo na leso de fibras C, aumento de SP e BDNF nasfibras A (mecanorreceptores de baixo limiar), assim comobrotamento dessas no local das conexes aferentes das fi-

Figura 2 Processo de Sensibilizao Perifrica

EstmuloLiberao deSubstnciaAlgognica

DOR- Reduo do limiar paraa dor dos nociceptores

j ativos- Ativao de nocicepto-res silentes

ROCHA, KRAYCHETE, LEMONICA E COL.


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bras C (lmina II), ampliando o campo receptivo do neurnioe facilitando a interpretao de estmulos mecnicos peri-fricos incuos como agressivos 25. Isso explica, por exemplo,a alodinia mecnica que acontece na neuralgia ps-herp-tica 26. Outra possibilidade seria a do brotamento de axnionoradrenrgico simptico no gnglio da raiz dorsal, ao re-

dor de neurnios de dimetro largo (fibras A), sugerindo ahiptese da ativao de fibras aferentes sensitivas aps aestimulao simptica 27. Alm disso, pode existir algumadesproporo entre as vias excitatrias e as de supressoda dor, com reduo da atividade inibitria da glicina, daGABA e dos opiides 24.

MECANISMOS CENTRAIS DA DOR

A transmisso dos estmulos nocivos atravs da medulaespinhal no um processo passivo. Os circuitos intrame-dulares tm a capacidade de alterar o estmulo e a conse-qente resposta dolorosa. A interao entre esses circuitosmedulares determinar as mensagens que atingiro ocrtex cerebral 21.Estudos clnicos e experimentais tm demonstrado que es-tmulos nocivos provocam alteraes no sistema nervosocentral, modificando os mecanismos desencadeados pelosestmulos aferentes. A estimulao persistente de nocicep-tores provoca dor espontnea, reduo do limiar de sensi-bilidade e hiperalgesia. Esta pode ser classificada comohiperalgesia primria e secundria. A hiperalgesia primria conceituada como sendo o aumento da resposta ao est-mulo doloroso no local da leso, enquanto a hiperalgesiasecundria aquela que se estende para reas adjacentes.

A presena de todos esses elementos sugere que a sen-sibilizao perifrica no o nico fenmeno responsvelpor todas essas mudanas e que deve haver envolvimentodo sistema nervoso central neste processo 21,28,29.A sensibilizao central implica alteraes dos impulsosperifricos, com adaptaes positivas ou negativas. Ocorrereduo do limiar ou aumento da resposta aos impulsosaferentes, descargas persistentes aps estmulos repetidose ampliao dos campos receptivos de neurnios do cornodorsal.Impulsos repetidos em fibras C amplificam sinais sensoriaisem neurnios espinhais, enviando mensagens para o en-cfalo 13. Leses perifricas induzem plasticidade em estru-turas supra-espinhais por meio de mecanismos queenvolvem tipos especficos de receptores para o glutamato.Aps a agresso tecidual h liberao de neurotransmis-sores, como substncia P, somatotastina, peptdeo gene-ticamente relacionado com a calcitonina, neurocinina-A,glutamato e aspartato. Essas substncias esto relacionadascom a ativao de potenciais ps-sinpticos excitatrios edos receptores N-metil-D-aspartato (NMDA) e no-NMDA.Estmulos freqentes dos aferentes geram a somao dospotenciais de ao e conseqente despolarizao ps-sinpticas cumulativa. Depois da ativao de receptores

NMDA pelo glutamato h remoo do on magnsio do in-terior do receptor e o influxo de clcio para a clula, do queresulta a amplificao e o prolongamento da resposta aoimpulso doloroso 30,31.O aumento do clcio tem como conseqncia a ativao daenzima xido ntrico-sintetase e a estimulao da transcri-

o de protoncogenes. Estes so genes localizados no sis-tema nervoso central e esto envolvidos na formao dedinorfinas e encefalinas. As encefalinas tm ao antinoci-ceptiva e esto envolvidas no processo de reduo da neu-roplasticidade e hiperalgesia. Entretanto, as dinorfinas tmum efeito complexo, j que possuem ao algognica eantinociceptiva 32,33.Estudos recentes tm sugerido que a ativao do c-fose c-junpromove a transcrio de RNA mensageiro responsvelpela sntese de protenas fundamentais, as quais esto en-volvidas na alterao da expresso fenotpica e, conseqen-temente, na perpetuao da hipersensibilidade neuronal 28,33

(Figura 3).A sensibilizao do corno dorsal da medula espinhal podeser de diferentes modalidades: wind up, sensibilizao sinp-tica clssica, potencializao de longo termo, fase tardia dapotenciao de longo termo e facilitao de longo termo 34.A sensibilizao sinptica clssica causada por uma se-qncia sincronizada de estmulos perifricos nociceptivosrepetidos por uma nica estimulao nociceptiva assncrona,aumentando a resposta de aferentes de fibras A e C (poten-cializao homossinptica) e de aferentes de fibras A no-es-timulados (potenciao heterossinptica). Isto conseqnciada liberao de aminocidos excitatrios, peptdeos e deneurotrofinas no corno dorsal da medula espinhal 35.

Os aminocidos excitatrios so representados pelo gluta-mato e pelo aspartato e se ligam a receptores especficosdo tipo ionotrpico ou metabotrpico. Os receptores ionotr-picos, ou receptores rpidos, so aqueles nos quais o lo-cal de ligao do neurotransmissor parte integrante deum canal inico, enquanto os receptores metabotrpicos oureceptores lentos so ligados protena G. Dentre os recep-tores para os aminocidos excitatrios destacam-se oAMPA, o cainato e o N-metil-D-aspartato (NMDA), que soionotrpicos, e o receptor Mrglu, que tem a sua ao me-diada pela protena G, sendo portanto um receptor metabo-trpico. Os peptdeos, a substncia P e o peptdeogeneticamente relacionado com a calcitonica (CGRP) ligam-se as neurocininas do tipo NK-1 e NK-2, enquanto asneurotrofinas possuem como receptores as tirocinases tipoA e B (trkA, trkB).Aps a liberao de aminocidos excitatrios, peptdeos eneurotrofinas e sua interao com receptores especficos,h a ativao de segundos mensageiros, do tipo AMPc, PKA,PKC, fosfotidilinositol, fosfolipase C, fosfolipase A2.. Isto pro-move a abertura de canais de clcio, e, conseqentemen-te, a produo de prostaglandinas e xido ntrico. Estesmigram do intracelular em direo fenda sinptica e cau-sam a liberao de glutamato, aspartato, substncia P e

DOR: ASPECTOS ATUAIS DA SENSIBILIZAO PERIFRICA E CENTRAL


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CGRP, contribuindo para a ampliao do processo lgico 34.O wind up o resultado da somao de potenciais sinp-ticos lentos aps estimulao aferente repetida de baixafreqncia, inferior a 5 Hz, e por tempo prolongado. Isto es-timula a liberao de neurotransmissores excitatrios,glutamato e aspartato, no corno dorsal da medula espinhale produz a despolarizao relacionada com a remoo dobloqueio voltagem-dependente exercido pelo magnsio nosreceptores NMDA. Ocorre, ento, aumento da condutividadeao clcio e a resposta dor, a cada estmulo repetido e damesma intensidade 36.

A potencializao de longo termo, embora mais estudada nohipocampo e nas reas corticais, pode ser decorrente de se-qncia de estmulos nociceptivos breves e de alta freqn-cia. Isso provocaria a ativao de receptores AMPA e NK1 e decanais de clcio, ocorrendo resposta ps-sinptica prolonga-da e excitatria, sobretudo em neurnios da lmina I 37.Os mecanismos que contribuem para o aumento da efic-cia da transmisso sinptica seriam decorrentes da fosfo-rilao dos receptores de membrana e das alteraes dotempo de abertura dos canais inicos, ou da formao e dotransporte de substncias excitatrias do interior da clula

Figura 3 Seqncia de Eventos que Levam a Sensibilizao dos Neurnios do Corno Dorsal aps Estimulao Nociceptiva Intensa eContinuada. Ativao intensa de neurnios aferentes primrios estimula a liberao de glutamato (Glu) e substncia P (SP). O receptorNMDA, em funo do papel do magnsio (Mg2+), inicialmente no-responsivo ao Glu; mas seguindo a despolarizao do receptor AMPApelo Glu no receptor metabotrpico estimula a ativao de fosfolipase C (PLC) mediada pela protena G, levando a hidrlise e transformaodo 4,5-bifosfato de fosfatidilinositol (PIP

2) em trifosfato de inositol (IP

3) e diacilglicerol (DAG). O DAG estimula a produo de protena cinase

C (PKC), a qual ativada na presena de elevados nveis de clcio (Ca 2+) intracelular. IP3estimula a liberao de clcio intracelular de

estoques intracelulares no retculo sarcoplasmtico. PKC aumentada induz o sustentado aumento da permeabilidade da membrana e, emconjuno com o aumento do Ca2+ intracelular, leva ao aumento da expresso de protoncogenes, como c-fose c-jun. As protenasproduzidas por esses protoncogenes codificam neuropeptdeos como as encefalinas (EKN), dinorfinas (DYN) e taquicininas (TK). Esseaumento tambm leva a ativao de fosfolipase A

2(PLA

2) e a ativao da sntese de xido ntrico (NOS) por um mecanismo clcio-

calmodulina dependente. PLA2

catalisa a converso de fosfatidilcolina (PC) para prostaglandina (PG), tromboxano (TX) e pela lipoxigenase(LO) para produzir leucotrienos (LT). NOS catalisa a produo de protena cinase e alteraes na expresso gentica. NO difunde-sedo interior da clula para o terminal do aferente primrio, onde aumenta a liberao de glutamato.

Interneurnioinibitrio (?)

Efeitosextracelulares (?)

GC

NO cGMP

SP SP Glu

GluGluSP

NK1 NMDA AMPANa

K+

Na

K+

Metabotrpico

PLCPIP2PLA2A A

PC

CO LO

LTTX, PG

CAM

CAM

PK

NOS

NO

Efeitos

intracelulares (?)

GC-cGMP

L-CI

L-Arg

Ca++

c-fosc-jun

DINENC

IP3

Ca++

Retculo endoplasmtico

IP3DAG

PKC

O2

ROCHA, KRAYCHETE, LEMONICA E COL.


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para a fenda sinptica. Alm disso, no corno dorsal da me-dula espinhal, as proteinocinases ativadas por mitgenos(MAPK) modulam a fosforilao dos receptores NMDA eAMPA, amplificando a resposta nociceptiva 38.A facilitao de longo termo envolve a ativao de fatores detranscrio e alteraes na transcrio. Os fatores de trans-

crio modulam a relao entre o complexo receptor-neuromediador e as alteraes na expresso gnica 39.O estmulo nociceptivo aciona a mesma cascata de recepto-res e segundo mensageiros descritos para a sensibilizaosinptica clssica; contudo, tambm provoca a expresso degenes de formao imediata c-fos (B,C,D), c-jun, de enzimasCOX-2 e de genes de resposta lenta que codificam a pr-dinorfina, o receptor NK1 e a trkB no corno dorsal da medu-la espinhal. Ocorre regulao ascendente das vias parasntese de citocinas, quimiocinas e molculas de adeso.Assim, h mudana fenotpica no gnglio da raiz dorsal 40.

RESPOSTAS SEGMENTARES E SUPRA-SEGMENTARES DOR

As fibras nociceptivas cruzam a linha mdia no nvel do cornodorsal da medula espinhal e ascendem pelos tratos espi-notalmicos, espinorreticular, espinomesenceflico, colunadorsal ps-sinptica e sistema espinopontoamigdaliano.Algumas dessas fibras terminam no ncleo talmicoventroposteromedial (VPM) e depois ascendem para o crtexcerebral somestsico (S1 e S2), crtex insular e cingularanterior. Outros neurnios projetam axnios para o hipot-lamo, formao reticular, substncia cinzenta periaquedutal,ncleo medial e intratalmico, e estruturas enceflicas an-

teriores que so responsveis pelas respostas neuroen-dcrinas e emocionais a dor 41.A ativao de fibras nociceptivas perifricas provoca migra-o retrgrada de fator de crescimento nervoso (NGF) paraa medula espinhal e induz resposta segmentar reflexa, comtransporte antergrado de substncia P para a periferia,ocasionando vasodilatao, aumento da permeabilidadevascular, atrao de clulas do sistema imune para o localda leso e degranulao de mastcitos com liberao dediversos neuromediadores. Desse modo, a substncia Pajuda na manuteno e na expanso do processo inflama-trio para o campo receptivo de fibras nervosas adjacentes rea lesada, constituindo a hiperalgesia secundria 42.Por outro lado, as fibras adrenrgicas, alm de contriburemcom o processo supracitado, aumentam a sensibilidade defibras nociceptivas ao de bradicinina. Potencializam es-ses efeitos, o vasoespasmo e o espasmo muscular, reflexosque proporcionam liberao de radicais cidos e, conse-qentemente, a reduo do limiar para disparos da fibranociceptiva 43.Do ponto de vista da resposta supra-segmentar, a pessoacom dor crnica parece apresentar possvel inabilidade deaumentar a secreo de hormnios do eixo hipotlamo-hipofisrio e adrenal ou amplificando a resposta simptica

ao lidar com o estresse fsico e emocional. Isso repercutenos nveis de secreo do cortisol, da adrenalina, da nora-drenalina, do hormnio do crescimento (GH), dos tireoidianose dos gonadais, tornando o sistema de defesa hipoativo.Esse modelo tenta explicar a fibromialgia ou a dor miofascial;nessas doenas, possvel que acontea aumento da se-

creo hipotalmica de CRH com regulao descendentedos receptores na hipfise, nveis elevados de ACTH e bai-xos de cortisol, e resistncia perifrica a ao do cortisol 44.O eixo hipotlamo-hipofisrio parece interagir, ento, com oprocesso doloroso em vrios nveis ou estgios. A ausn-cia de glicocorticide pode: 1) diminuir a converso doglutamato, neurotransmissor excitatrio, para glutamina,aumentando a neurotoxicidade do glutamato no sistemanervoso central; 2) aumentar a produo de fator de cresci-mento nervoso (NGF) e da substncia P; e 3) aumento daproduo de citocinas e, conseqentemente, de NGF 45.A leso do tecido e do neurnio resulta em sensibilizao

de nociceptores e facilitao da conduo nervosa perifri-ca e central. O estudo desses mecanismos poder elucidarem um futuro prximo meios para o diagnstico e o trata-mento de sndromes dolorosas agudas e crnicas.

Pain: Current Aspects on Peripheraland Central Sensitization

Anita Perptua Carvalho Rocha, M.D.; Durval CamposKraychete, TSA, M.D.;Lino Lemonica, TSA, M.D.; Ldia Raquelde Carvalho, M.D.; Guilherme Antnio Moreira de Barros,TSA, M.D.; Joo Batista dos Santos Garcia, TSA, M.D.; RiokoKimiko Sakata, TSA, M.D.

INTRODUCTION

Although the International Association for the Study of Pain(IASP) defined pain as a subjective sensation related totissue injury, there is evidence that this association mightnot occur. Headache and chronic pelvic pain, for example,seem to exist without tissue damage that can be detected bythe diagnostic methods currently available, favoring thehypothesis that there can be neurofunctional changes res-

tricted to the biomolecular level, with the little known inte-raction among neuromediators, neurotransmitters, andsignal transducers in a network of billion of synapses, ma-king it difficult to understand the etiology of pain 1. On theother hand, trauma and stimulation of the peripheral or cen-tral nervous system can also change immune responses. Asa consequence, peptides and receptors are activated,followed by the translation of the signal to the intracellularenvironment. In this context, advances in the knowledge ofthe neuranatomy of conduction pathways, neuropharma-cology, and pathophysiology of pain facilitate the development

PAIN: CURRENT ASPECTS ON PERIPHERAL AND CENTRAL SENSITIZATION


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of research on new treatment modalities. Thus, effectiveanalgesia for painful syndromes is still a great challenge.In Brazil 2 and in other countries 3,4, 10% to 50% of the peopleseek clinics to treat their pain 5-8. In Brazil, pain is present inover 70% of the patients who seek medical attention forseveral reasons, and is the main reason for the medical visit

in one third of the cases. This argument stresses the impor-tance of searching for elements that could lead to a betterapproach of acute and chronic pain.The aim of this review was to discuss the pathophysiologyof pain, emphasizing the peripheral and central mechanismsof pain transmission.

PERIPHERAL PAIN MECHANISMS

The first step on the sequence of events that originate thepainful phenomenon is the transformation of aggressivestimuli in action potentials that are transmitted from the

peripheral nerve fibers to the central nervous system9

.Specific pain receptors are located at the nerve endings ofA and C nerve fibers 10,11 and, when they are activated, thereare changes in their membranes, allowing the deflagrationof the action potentials.Nerve endings of nociceptive A and C fibers (nociceptors)are capable to translate an aggressive thermic, chemical, ormechanical stimulus into an electrical stimulus that will betransmitted to the central nervous system and interpreted inthe cerebral cortex as pain. The A fibers are myelinated whileC fibers are non-myelinated; therefore, they are capable oftransmitting painful stimuli at different speeds. Due to thepresence of the myelin shaft, A fibers transmit the painful

stimulus fast, while C fibers are responsible for the slowtransmission of pain. Both are classified as subtypes A1,A2, C1, and C2 (Table I). The type of nociceptive fiber seems

to be related to distinct peripheral changes on the differentpainful syndromes and could, in the future, contribute for amore effective pain treatment.The nociceptors are then sensitized by the action of chemicalsubstances, known as angiogenic, present in the tissue envi-ronment 12: acetylcholine, bradykinin, histamine, serotonin,

leukotriene, substance P, platelet activating factor, acid ra-dicals, potassium ions, prostaglandins, thromboxane, inter-leukins, tumor necrosis factor (TNF), nerve growth factor(NGF), and cyclic adenosine monophosphate (cAMP) 13-15 (Fi-gure 1).When the stimulus causes tissue injury, the inflammatoryprocess is triggered, which is followed by repair. Damagedcells release their enzymes that, once in the extracellularenvironment, degrade long chain fatty acids and act on kini-nogens, originating the kinins. Kinins are small polypeptidesof

2-calicrein present in the plasma or body fluids. Kallikrein

is a proteolytic enzyme activated by inflammation and other

chemical or physical effects on blood or tissues. Onceactivated, kallikrein works immediately on the 2-globulin,

liberating the kinin called kallidin that is then converted inbradykinin by tissue enzymes. Once formed, bradykinin cau-ses intense dilation of the arterioles and increases capillarypermeability, contributing to the dissemination of inflam-mattion 16.The action of phospholipase A on the cell membrane causesthe release of arachidonic acid, which is metabolized bythree enzymatic systems: cyclooxigenase that originatesprostaglandins, thromboxanes, and prostacyclins; lipoxige-nase that induces the production of leukotrienes and lipoxins;and P-450 cytochrome that originates the products of the

epoxigenase pathway. These substances, especially pros-taglandins E

2(PGE

2), decrease the excitability threshold of

nociceptors 17. Inflammatory cells, macrophages, and leu-

Table I Subtypes of A and C Fibers

Fiber Type Characteristics

Type I A fibers Respond to temperatures of about 52C,they are not sensitive to capsaicin andtheir response is modulated by VRL-1receptors

Type II A f ibers Sensit ive to temperatures of about 43C,

activated by capsaicin, and activate,through VR1 receptors, non-selectivecationic channels permeable to calcium

Type I C fibers Con ta in substance P and CGRP andexpress thyrokinase A receptors for thenerve growth factor. They respond tocapsaicin and protons

Type II C fibers E xpr es s p ur ine rgi c P 2X3

receptor foradenosine and a group of surfacecarbohydrates, -D-galactose, capable ofbinding lectin IB-4, and have selectivesensitivity to protons

Cellularmembrane

Bradykinin

Lesion

Acetylcholine

HistamineEnzymes

H+

TNF-K+

Substance PSerotonin

ProstaglandinsAlgogenic

substances

Figure 1 Release of Algogenic Substances After Tissue Injury

ROCHA, KRAYCHETE, LEMONICA ET AL.


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cocytes release cytokines that contribute to the migration ofnew cells to the site of injury. There is production and relea-se of interleukins 1 and 6, tumor necrosis factor, selectin,chemotactic factors, nitric oxide, and oxidizing substances.New receptors are then recruited, and participate in theinflammatory process. Substance P and neurokinin A cause

vasodilation and increase vascular permeability, which alsofor maintaining the inflammatory process 18.However, bradikinin, prostaglandin E2, nerve growth factor(NGF), and interleukins seem to be fundamental in periphe-ral nociception. Prostaglandin and bradykinin cause changesin specific receptors (TRPV1) attached to ligand-dependention channels through the activation of cAMP and proteinkinases A (PKA) and C (PKC), reducing the post-hyperpo-larization time of the neural membrane, and decreasing thetriggering threshold of the nervous fiber.Neurotrophins increase the synthesis, anterograde axonaltransport, and the amount of SP and CGRP in type 1 C fibers,and reduce the activity of gamma-aminobutyric acid (GABA),both in peripheral and central nerve endings. They alsocause changes in the vanilloid receptors (VR1) of A fibersattached to ligand-dependent ion channels and trigger pro-tein kinases activated by mitogens (MAPK) that can phospho-rilate cAMP and initiate the genetic transcription responsiblefor phenotypic changes that contribute to the increase insynaptic efficacy.If the aggression is persistent, it leads to changes in theperipheral nervous system and sensitizes nerve fibers, withconsequent hyperalgia and increase in the levels of cAMPand calcium in the nociceptors. This phenomenon is secon-dary to the action of inflammatory mediators and consequent

spontaneous activity of neurons, increase in the response tosuprathreshold stimuli, and reduction of the activationthreshold of nociceptors 18-20. An especial type of nociceptor,known as silent nociceptor, is activated after inflammation orafter tissue injury. It is estimated that 40% of C fibers and30% of A fibers contribute with silent nociceptors. After therelease of chemical products in the lesion, these receptors,previously silent, are activated by thermal and mechanicalstimuli, developing spontaneous discharges, being capableof an intense response to nociceptive and non-nociceptivestimuli 21-22 (Figure 2).In short, tissue injury results in accumulation of arachidonicacid metabolites. The production of prostaglandins and leuko-trienes leads to the degranulation of mast cells and directactivation of nerve fibers, macrophages and lymphocytes.Mediators, such as potassium, serotonin, substance P,histamine, and kinins are released. There are changes invascular permeability, local blood flow, resulting in theclassical signs of inflammation, like erythema, increasedtemperature, edema, and functional impotence. The processof peripheral sensitization is initiated with the consequentexacerbation of the response to the painful stimulus 20-22.Peripheral neuromediators prolong the depolarization of theneural membrane, with the consequent increase of sodium

and calcium channels conductivity, and a decrease in theinflux of potassium and chloride.Sodium channels are involved in the genesis of neuronalhyperexcitability and can be classified in two large groups:those sensitive to tetrodotoxin (TTXs), present in A fibers, inthe entire nervous system, and in the dorsal root ganglion;and those resistant to tetrodotoxin (TTXr), found especially inC fibers of the dorsal root ganglion 23. Although the peripherallesion of C fiber decreases SP, neurotrophins (BDNF),

receptors (VR1 and P2X3), and high-voltage type N calciumchannels in the dorsal horn of the spinal cord, there isupregulation of type III TTXs channels, and sodium channels(TTXr) are translocated from the cell body to the neuroma,facilitating the increase in nervous excitability 24. Thishappens if the nerve fiber is intact (inflammation), i.e., thereis an increase in excitatory neuromediators in the dorsalhorn of the spinal cord and greater expression of sodiumchannels (TTXr), which facilitates neuronal hyperexcitabilityand hinders the response to the treatment with localanesthetics 24.In both situations described, especially in the lesion of Cfibers, there can also be an increase in SP and BDNF in Afibers (low threshold mechanoreceptors), as well as buddingof those at the connections of afferent C fibers (lamina II),increasing the receptive field of the neuron and facilitating theinterpretation of harmless stimuli as aggressive 25. Thisexplains, for example, the mechanical allodynia that occursin post-herpetic neuralgia 26. Other possibility would be thebudding of sympathetic noradrenergic axons at the dorsalroot ganglion, around large diameter neurons (A fibers),suggesting the hypothesis of activation of afferent sensitivefibers after the sympathetic stimulation 27. Besides, there canalso be a disproportion between excitatory and pain sup-

Figure 2 Process of Peripheral Sensitization

StimulusRelease ofAlgogenicSubstance

PAIN- Reduction of the painthreshold in the activenociceptors- Activation of silent no-ciceptors



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pressing pathways, with a decrease in the inhibitory activityof glycine, GABA, and opioids 24.

CENTRAL PAIN MECHANISMS

The transmission of noxious stimuli in the spinal cord is not

a passive process. Intraspinal circuits have a capacity tochange both the stimulus and painful response. The inte-raction among the intramedullary circuits determines whichmessages will reach the cerebral cortex 21.Clinical and experimental studies have demonstrated thatnoxious stimuli cause changes in the central nervoussystem, which modify the mechanisms triggered by afferentstimuli. Persistent stimulation of nociceptors causes spon-taneous pain, reduces the sensitivity threshold, and causeshyperalgesia. This can be divided in primary and secondaryhyperalgesia. Primary hyperalgesia is defined as the in-creased response to the painful stimulus at the site of injury,while secondary hyperalgesia is the extension of that res-ponse to adjacent areas. The presence of all of those ele-ments suggests that peripheral sensitization is not the onlyphenomena responsible for them, and that the central ner-vous system must be involved in this process 21,28,29.Central sensitization implies changes in peripheral impul-ses, with positive or negative adaptations. There is a reductionin the threshold or an increase in the response to afferentimpulses, persistent discharges after repeated stimuli, andwidening of the receptive fields of dorsal horn neurons.Repeated impulses in C fibers amplify sensorial signals inspinal neurons, sending messages to the brain 13. Periphe-ral lesions induce plasticity in supraspinal structures through

mechanisms that encompass specific types of gluatamatereceptors. Neurotransmitters, such as substance P, soma-tostatin, peptide genetically linked to calcitonin, neurokinin A,glutamate, and aspartate are released after tissue injury.These substances are connected to the activation of exci-tatory post-synaptic potentials, and of N-methyl-D-aspartate(NMDA) and non-NMDA receptors. Frequent stimulation ofafferent fibers generates a summation of action potentialsand the consequent cumulative pos-synaptic depolarization.After activation of NMDA receptors by glutamate, the ionmagnesium is removed from the receptor, leading to theinflux of calcium into the cell, amplifying and prolonging theresponse to the painful stimulus 30,31.The increase in calcium concentration leads to activation ofnitrous oxide synthase and stimulation of the transcription ofprotooncogenes. These genes are located in the centralnervous system, being involved in the formation of dinorphinsand enkephalins. Enkephalins are antinociceptive andconnected to the reduction of neuroplasticity and hyperal-gia 32,33. However, dinorphins have a complex mechanism ofaction, since they have algogenic and antinociceptvie actions.Recent studies have suggested that the activation of f-fosand c-junpromotes the transcription of the messenger RNAresponsible for the synthesis of fundamental proteins invol-

ved in changing the phenotypic expression, and the conse-quent perpetuation of neuronal hypersensitivity 28,33 (Figure 3).The sensitization of the dorsal horn of the spinal cord can beof several modalities: wind up, classical synaptic sensiti-zation, long-term potentiation, late phase of the long-termpotentiation, and long-term facilitation 34.

The classical synaptic sensitization is caused by a synchro-nized sequency of repeated peripheral nociceptive stimuli forone asynchronous nociceptive stimulus, increasing theafferent response of A and C fibers (homosynaptic potentia-tion) and the afferent response of non-stimulated A fibers(heterosynaptic potentiation). This is a consequence of therelease of excitatory amino acids, peptides, and neurotro-phins in the dorsal horn of the spinal cord 35.Excitatory amino acids, represented by glutamate and as-partate, bind to specific ionotropic or metabotropic receptors.In ionotropic, or fast, receptors the neurotransmitter bindingsite is an integral part of an ion channel, while metabotropic,or slow, receptors are bound to protein G. Among the recep-tors for excitatory amino acids, we should mention AMPA,cainate, and N-methyl-D-aspartate (NMDA), that are ionotro-pic, and the Mrglu receptor, whose action is mediated byprotein G, making it a metabotropic receptor. Peptides, subs-tance P, and calcitonin gene-related peptide (CGRP) bind toneurokinins type NK-1 and NK-2, while neurotrophins bindto thyrokinases types A and B (trkA and trkB) receptors.After the release of excitatory amino acids, peptides, andneurotrophins and their binding to specific receptors, thereis activation of second messengers, such as cAMP, PKA,PKC, phosphatidylinositol, phospholipase C, and phospho-lipase A2. This opens the calcium channels and, conse-

quently, the production of prostaglandins and nitrous oxide,which migrate from the intracellular environment to the sy-naptic cleft and cause the release of glutamate, aspartate,substance P, and CGRP, contributing to the amplification ofthe painful process 34.Wind up is the summation of slow synaptic potentials afterrepeated low frequency, below 5 Hz, stimulation of theafferent fibers for a prolonged time. This triggers the releaseof excitatory neurotransmitters, glutamate, and aspartate inthe dorsal horn of the spinal cord and produces depola-rization secondary to the removal of the voltage-dependentblockade caused by the presence of magnesium in NMDAreceptors. There is an increase in calcium conductivity andresponse to pain to each repeated stimulus of the sameintensity 36.Although long-term potentiation is better known in the hippo-campus and cortical areas, it may be the result of a sequenceof short, high frequency nociceptive stimuli. This wouldactivate AMPA and NK1 receptors and calcium channels,leading to the prolonged, excitatory post-synaptic response,especially in the neurons in lamina I 37.The mechanisms that contribute to the increased efficacy ofsynaptic transmission would be the result of phosphorylationof membrane receptors and changes in the opening time of



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ion channels, or the formation and transport of excitatorysubstances from the cell to the synaptic cleft. Besides, pro-teinokinases activated by mitogens (MAPK) in the dorsalhorn of the spinal cord modulate the phosphorylation ofNMDA and AMPA receptors, amplifying the nociceptive res-ponse 38.Long-term facilitation involves the activation of transcriptionfactors and changes in transcription. Transcription factorsmodulate the relationship between the receptor-neurome-diator complex and changes in gene expression 39.

The nociceptive stimulus triggers the same receptor cascadeand second messengers described previously for the clas-sical synaptic sensitization, but it also triggers the expres-sion of immediate early genes c-fos (B, C, D), c-jun, COX-2enzymes, and slow response genes that encode pro-dinorphin, NK1 receptor, and trkB in the dorsal horn of thespinal cord. There is upregulation of the pathways for thesynthesis of cytokines, chemokines, and adhesion mole-cules. This causes phenotypic changes in the dorsal rootganglion 40.

Figure 3 Sequence of Events that Lead to Sensitization of the Neurons in the Dorsal Horn After Intense and Continuous Nociceptive Stimulation.The intense activation of primary afferent neurons triggers the release of glutamate (Glu) and substance P (SP). Due to the role ofmagnesium (Mg+2), the NMDA receptor is not responsive to Glu initially; but the depolarization of AMPA receptors by the presence of Gluin the metabotropic receptor activates phospholipase C (PLC), which is mediated by protein G, causing hydrolysis and transformation ofphosphatidyilinositol 4,5-biphosphate (PIP

2) in inositol triphosphate (IP

3) and diacylgyicerol (DAG). Diacylglycerol stimulates the production

of protein kinase C (PKC), which is activated in the presence of elevated intracellular calcium (Ca +2) levels. Inositol triphosphate stimulatesthe release of calcium from intracellular storage sites in the sarcoplasmic reticulum. The increase in PKC induces the sustained increasein membrane permeability and, along with an increase in intracellular Ca+2, increases the expression of protooncogenes, such as c-fosand c-jun. The proteins produced by these protooncogens encode neuropeptides, such as enkephalins (EKN), dinorphins (DYN), andtachykinin (TK). This increase also leads to the activation of phospholipase A

2(PLA

2) and activation of the nitric oxide synthetase (NOS)

by a calmodulin-dependent mechanism. Phospholipase A2

catalyzes the conversion of phosphatidilcholine (PC) to prostaglandin (PG), andthromboxane (TX) and to produce leukotrienes (LT) by lypoxigenase (LO). Nitric oxide synthetase catalyzes the production of protein kinaseand leads to changes in the genetic expression. Nitric oxide diffuses from the intracellular environment to the terminal of the primary afferentwhere it increases the release of glutamate

Inhibitoryinterneuron (?)

Extracellulareffects (?)

GC

NO cGMP

SP SP Glu

GluGluSP

NK1 NMDA AMPANa

K+

Na

K+

Metabotropics

PLCPIP2PLA2A A

PC

CO LO

LTTX, PG

CAM

CAM

PK

NOS

NO

Intracellular

effects (?)

GC-cGMP

L-CI

L-Arg

Ca++

c-fosc-jun

DINENC

IP3

Ca++

Endoplasmic reticulum

IP3DAG

PKC

O2



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SEGMENTAR AND SUPRA-SEGMETAR RESPONSESTO PAIN

Nociceptive fibers cross the midline at the level of dorsalhorn of the spinal cord and ascend through the spinotha-lamic, spinoreticular, and spinomesencephalic tracts, post-

synaptic posterior column, and spino-ponto-amigdalasystem. Some of those fibers end at the ventroposteromedialthalamic nucleus (VPM) and ascend posteriorly to the so-mesthesic (S1 and S2) cerebral cortex, insular cortex, andposterior cingular cortex. Other neurons project their axonsto the hypothalamus, reticular formation, periaqueductal graymatter, medial and intrathalamic nucleus, and anterior brainstructures responsible for the neuroendocrine and emotionalresponses to pain 41.The activation of peripheral nociceptive fibers leads to re-trograde migration of nerve growth factor (NGF) to the spinalcord and induces reflex segmental response with antero-grade transport of substance P to the periphery, causingvasodilation, increase in vascular permeability, attraction ofcells of the immune system to the site of injury, and degra-nulation of mast cells and the release of several neuro me-diators. Thus, substance P helps the maintenance andexpansion of the inflammatory process to the receptive fieldof nerve fibers adjacent to the site of injury, constituting thesecondary hyperalgia 42.On the other hand, adrenergic fibers contribute not only tothe process described above but also increase the sensi-tivity of nociceptive fibers to bradykinin. Vasospasm, muscu-lar spasm, reflexes that trigger the release of acid radicalsand, consequently, reduce the discharge threshold for noci-

ceptive fibers, potentiate those effects 43.In supra-segmental response, the individual with chronicpain seems to have a possible inability to increase thesecretion of the hypothalamus-pituitary-adrenal axis hormo-nes or increase the sympathetic response when dealing withphysical and emotional stress. This is reflected on the in-creased levels of cortisol, adrenaline, noradrenaline, growthhormone (GH), and thyroid and gonadal hormones, decrea-sing the activity of the defense system. This model tries toexplain fibromyalgia or myofascial pain; it is possible thatthere is an increase in the hypothalamic secretion of CRHwith down regulation of receptors in the pituitary, increasedlevels of ACTH and low levels of cortisol, and peripheralresistance to cortisol 44.The hypothalamus-pituitary axis seems to interact with thepainful process in several levels or stages. The absence ofglucocorticoids can: 1) decrease the conversion of glutama-te, an excitatory neurotransmitter, to glutamine, increasing theneurotoxicity of glutamate in the central nervous system; 2)increase the production of nerve growth factor (NGF) andsubstance P; and 3) increase the production of cytokinesand, consequently, of NGF 45.Tissue and neuronal injury result in sensitization of noci-ceptors and facilitate peripheral and central nervous systems

conduction. The study of those mechanisms may, in the fu-ture, elucidate ways to diagnose and treat acute and chronicpain syndromes.

REFERNCIAS REFERENCES

01. Lacerte M, Shah RV - Interventions in chronic pain management.1. Pain concepts, assessment, and medicolegal issues. ArchPhys Med Rehabil, 2003;84:S35-S38.

02. Turk DC, Melzack R - The Measurement of Pain and the Assess-ment of People Experiencing Pain. Handbook of Pain Assessment.New York, Guildford, 1992;3-12.

03. Jacobsson L, Lindgarde F, Manthorpe R - The commonest rheu-matic complaints of over six week duration in a twelve-monthperiod in a defined Swedish population. Prevalences and rela-tionships. Scand J Rheumatol, 1989;18:353-360.

04. James FR, Large RG, Bushnell JA et al - Epidemiology of pain inNew Zealand. Pain, 1991;44:279-283.

05. Bonica JJ - Treatment of Cancer Pain: Current Status and FutureNeeds, em: Dubner R, Cervero F - Advances in Pain Research

and Therapy, 1985;589-616.06. Bovim G, Schrader H, Sand T - Neck pain in the general popu-

lation. Spine, 1994;19:1307-1309.07. Brattberg G - Epidemiological studies of pain. Acta Universitatis

Upsaliensis, Comprehensive Summaries of Upsala Dissertationsfrom the Faculty of Medicine, 1989;196:52.

08. Walco GA, Oberlander TM - Musculoskeletal Pain Syndromes inChildren, em: Schechter NL, Berde CB, Yaster M - Pain in Infants,Children, and Adolescents. Baltimore, Williams & Williams1996;459-472.

09. Besson P, Perl ER - Responses of cutaneous sensory units withunmyelinated fibers to noxious stimuli. J Neurophysiol, 1969;32:1025-1043.

10. Levine JD, Taiwo Y - Inflammatory Pain, em: Wall PD, Melzack R,Bonica JJ - Textbook of Pain. 3rd ed., Edinburgh, Scothand, Chur-

chill Livingstone, 1994;45-56.11. Loewenstein WR - Mechano-Electric Transduction in the Paci-

nian Corpuscle: Initiation of Sensory Impulses in Mechanore-ceptors, em: Autrum H - Handbook of Sensory Physiology. Berlin.Springer-Verlag, 1971;267-290.

12. Webster KE - Somaesthetic pathways. Br Med Bull, 1977;33:113-120.

13. Bedbrook GM - Injuries of the Thoracolumbar Spine with Neu-rological Symptoms, em: Vinken PJ, Bruyn GW - Handbook ofClinical Neurology Amsterdam. 25th ed., North-Holland, 1976;437-466.

14. Campbell JN, Raja SN, Cohen RH et al - Peripheral NeuralMechanisms of Nociception, em: Wall PD, Melzack R - Textbookof Pain. Edimburgh, Scotland, Churchill Livingstone, 1989;22-45.

15. Piotrowski W, Foreman JC - Some effects of calcitonin gene-related peptide in human skin and on histamine release. Br JDermatol, 1986;114:37-46.

16. Guyton AC, Hall JE - Controle Local do Fluxo Sanguneo pelosTecidos, em: Guyton AC, Hall JE - Tratado de Fisiologia Mdica.Rio de Janeiro, Guanabara Koogan, 2002;166-173.

17. OBanion MK - Cyclooxygenase-2: molecular biology, pharma-cology, and neurobiology. Crit Rev Neurobiol, 1999;13:45-82.

18. Ferreira SH - Hiperalgesia inflamatrial, xido ntrico y controlperifrico del dolor. Rev Latino Americana de Dolor, 1995;12:6-17.

19. Fletcher D, Kayser V, Guilbaud G - Influence of timing of admi-nistration on the analgesic effect of bupivacaine infiltration incarrageenin-injected rats. Anesthesiology, 1996;84:1129-1137.



12/12


20. Aida S, Baba H, Yamakura T et al - The effectiveness ofpreemptive analgesia varies according to the type of surgery: arandomized, double-blind study. Anesth Analg, 1999;89:711-716.

21. Woolf CJ - Recent advances in the pathophysiology of acutepain. Br J Anaesth, 1989;63:139-146.

22. Woolf CJ, Chong MS - Preemptive analgesia treating postope-rative pain by prevention the establishment of central sensi-

tization. Anesth Analg, 1993;77:362-379.23. Lai J, Gold MS, Kim CS et al - Inhibition of neuropathic pain bydecreased expression of the tetrodotoxin-resistant sodiumchannel, Nav1.8. Pain, 2002;95:143-152.

24. McMahon SB - Neuropathic Pain Mechanisms, em: GiamberardinoMA Pain 2002 an Updated Review: Refresher CourseSyllabuss. Seattle, IASP, 2002;155-161.

25. Mannion RJ, Doubell TP, Coggeshall RE et al - Collateral sproutingof uninjured primary afferent A-fibers into the superficial dorsalhorn of the adult rat spinal cord after topical capsaicin treatmentto the sciatic nerve. J Neurosci, 1996;16:5189-5195.

26. Rowbotham MC, Fields HL - The relationship of pain, allodyniaand thermal sensation in post-herpetic neuralgia. Brain, 1996;119:347-354.

27. Choi B, Rowbotham MC - Effect of adrenergic receptor acti-

vation on post-herpetic neuralgia pain and sensory disturbances.Pain, 1997;69:55-63.28. Alan NS - Controle da dor no perodo perioperatrio. Clin Cirurg

Am Norte, 1999;79:197-211.29. Dickenson AH, Sullivan AF - Subcutaneous formalin-induced

activity of dorsal horn neurons in the rat: differential responseto an intrathecal opiate administered pre or pos formalin. Pain,1987; 30:349-360.

30. Woolf CJ - Somatic pain pathogenesis and prevention. Br JAnaesth, 1995;75:169-176.

31. Dickenson AH - Recent advances in the physiology and phar-macology of pain: plasticity and its implications for clinical anal-gesia. J Psychopharm, 1991;5:342-351.

32. Coderre TJ, Vaccarino AL, Melzack R - Central nervous systemplasticity in the tonic pain response to subcutaneous formalin

injection. Brain Res, 1990;535:155-158.33. Malmberg AB, Yaksh TL - Hyperalgesia mediated by spinalglutamate or substance P receptor blocked by spinal cyclooxy-genase inhibition. Science, 1992;257:1276-1279.

34. Ji RR, Kohno T, Moore KA et al - Central sensitization and LTP:do pain and memory share similar mechanisms? Trends Neurosci,2003;26:696-705.

35. Woolf CJ, Salter MW - Neuronal plasticity: increasing the gain inpain. Science, 2000;288:1765-1769.

36. Li J, Simone DA, Larson AA - Windup leads to characteristics ofcentral sensitization. Pain, 1999;79:75-82.

37. Randic M, Jiang MC, Cerne R - Long-term potentiation and long-term depression of primary afferent neurotransmission in the ratspinal cord. J Neurosci, 1993;13:5228-5241.

38. Ji RR, Samad TA, Jin SX et al - p38 MAPK activation by NGF inprimary sensory neurons after inflammation increases TRPV1levels and maintains heat hyperalgesia. Neuron, 2002;36:57-68.

39. Sandkuhler J - Learning and memory in pain pathways. Pain,2000;88:113-118.

40. Hunt SP, Pini A, Evan G - Induction of c-fos-like protein in spinalcord neurons following sensory stimulation. Nature, 1987; 328:

632-634.41. Basbaum A, Bushnell MA - Pain: Basic Mechanisms, em:Giamberardino MA Pain 2002 an updated Review: RefresherCourse Syllabuss. 1st ed., Seattle, IASP, 2002;3-7.

42. Otten U, Goedert M, Mayer N et al - Requirement of nerve growthfactor for development of substance P-containing sensoryneurones. Nature, 1980;287:158-159.

43. Basbaum AI - Distinct neurochemical features of acute andpersistent pain. Proc Natl Acad Sci, 1999;96:7739-7743.

44. Neeck G - Pathogenic mechanisms of fibromyalgia. Ageing ResRev, 2002;1:243-255.

45. Dessein PH, Shipton EA, Stanwix AE et al - Neuroendocrinedeficiency-mediated development and persistence of pain infibromyalgia: a promising paradigm? Pain, 2000;86:213-215.

RESUMENRocha APC, Kraychete DC,Lemonica L, Carvalho LR, Barros GAM,Garcia JBS, Sakata RK Dolor: Aspectos Actuales de la Sensibili-zacin Perifrica y Central.

JUSTIFICATIVA Y OBJETIVOS:Las recientes investigaciones sehan centrado en la plasticidad bioqumica y estructural del sistema

nervioso proveniente de la lesin tisular. Los mecanismos involu-

crados en transicin del dolor agudo para crnico son complejos

e involucran la interaccin de sistemas receptores y el flujo de iones

intracelulares, sistemas de segundo mensajero y nuevas cone-

xiones sinpticas. El objetivo de este artculo fue discutir los nuevos

mecanismos que envuelven la sensibilizacin perifrica y central.

CONTENIDO:La lesin tisular provoca un aumento en la respuestade los nociceptores, llamada sensibilizacin o facilitacin. Esos fen-

menos empiezan despus de la liberacin local de mediadores

inflamatorios y de la activacin de clulas del sistema inmune o de

receptores especficos en el sistema nervioso perifrico y central.

CONCLUSIONES:Las lesiones del tejido y de las neuronasresultan en una sensibilizacin de nociceptores y en la facilitacin

de la conduccin nerviosa central y perifrica.


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