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492 Revista Brasileira de AnestesiologiaVol. 58, No 5, Setembro-Outubro, 2008

Rev Bras Anestesiol ARTIGO DE REVISO2008; 58: 5: 492-505 REVIEW ARTICLE

RESUMOKraychete DC, Gozzani JL, Kraychete AC Dor Neuroptica As-pectos Neuroqumicos.

JUSTIFICATIVA E OBJETIVOS:A dor neuroptica causada porleso ou inflamao do sistema nervoso. sndrome complexa,com mecanismos biolgicos pouco esclarecidos, envolvendo teo-rias inflamatrias e imunes. O objetivo desta reviso foi descre-ver os principais fatores biolgicos relacionados com a dorneuroptica, associando de forma lgica as hipteses sugeridaspela literatura.

CONTEDO:Foram descritos os principais neuromediadores, ca-nais inicos e clulas, incluindo as do sistema imune envolvidosna excitabilidade neuronal, assim como enfatizada possvel se-qncia de ativao ou interao desses agentes na alteraoneuroplstica decorrente da agresso ao nervo.

CONCLUSES:Do estudo, foi possvel concluir que os avanos noconhecimento da fisiopatologia da dor neuroptica podem determi-nar novos alvos para abordagem farmacolgica dessa sndrome.

Unitermos: DOR: neuroptica; FISIOLOGIA: neurotransmissores.

SUMMARYKraychete DC, Gozzani JL, Kraychete AC Neuropathic Pain Neurochemical Aspects.

BACKGROUND AND OBJECTIVES:Neuropathic pain is causedby damage or inflammation of the nervous system. It is a complexsyndrome and its biological mechanisms, involving inflammatoryand immunologic theories, are not clear. The objective of this reviewwas to describe the main biologic factors associated with neu-ropathic pain, making a logical association between hypothesessuggested in the literature.

CONTENTS:The main neuromediators, ion channels, and cells,including cells in the nervous system involved in neuronal excitationare described, and the possible activation sequence or interactionamong those agents in the neoplastic change secondary to nervedamage are emphasized.

CONCLUSIONS:It was possible to conclude that the advances onthe knowledge of the pathophysiology of neuropathic pain can de-termine new pharmacologic approaches for this syndrome.

Key Words: PAIN: neuropathic; PHYSIOLOGY: neurotransmitters.

INTRODUO

A dor neuroptica definida como dor decorrente de lesoou disfuno do nervo e de modo mais amplo, como conse-qncia de leso ou doena do sistema somestsico 1. uma sndrome complexa, com mecanismos biolgicos pou-co esclarecidos, envolvendo teorias inflamatrias e imunes.

MODELOS EXPERIMENTAIS PARA ESTUDO DA DORNEUROPTICA

A maioria dos modelos experimentais descritos na literatu-ra foi em ratos e se desenvolveu a partir de leses perifri-cas traumticas, metablicas ou txicas:1. Ligadura do nervo espinal (SNL) um ou mais nervos

espinais que vo para a pata so apertados por lao ecortados.

2. Ligadura isquitica parcial (PSL) parte do nervo is-quitico apertada por lao.

3. Leso constritiva crnica (CCI) inclui a colocao dequatro ligaduras apertadas com fio cromado no nervoisquitico.

4. Leso limitada do nervo (SNI) so cortados os nervosfibular e tibial posterior e poupado o sural. Essa tcnicaprovoca alteraes comportamentais de longa durao.

Outros mtodos incluem a injeo intraperitoneal de estrep-tozocina para mimetizar neuropatia diabtica ou de paclita-xel e vincristina para neuropatia induzida por quimioterapia.Os modelos para dor central usam a contuso (trauma uti-lizando a fora do impacto com deslocamento tissular), ouleses isqumicas por compresso lenta por meio de pina-mento ou da insuflao com balonetes. Mtodos citotxicosempregam a injeo de anlogos de glutamato (cainato) oude substncias que permitem a leso de locais especficosda substncia cinzenta. As tcnicas descritas visam a pro-vocar hiperalgesia mecnica e trmica 2,3.

Dor Neuroptica Aspectos Neuroqumicos*Neuropathic Pain Neurochemical Aspects

Durval Campos Kraychete, TSA1, Judymara Lauzi Gozzani, TSA2, Angiolina Campos Kraychete3

*Recebido da (Received from) Faculdade de Medicina da Universidade Fe-deral da Bahia (UFBA), Salvador, BA

1. Professor Adjunto de Anestesiologia UFBA; Coordenador do Ambulatriode Dor UFBA

2. Editor-Chefe da Revista Brasileira de Anestesiologia; Coordenador do Ser-vio de Dor da Faculdade de Cincias Mdicas da Santa Casa de So Pau-lo, SP3. Mdica Estagiria do Ambulatrio de Dor UFBA

Apresentado (Submitted) em 16 de fevereiro de 2008Aceito (Accepted) para publicao em 23 de junho de 2008

Endereo para correspondncia (Correspondence to):Dr. Durval Campos KraycheteRua Rio de So Pedro, 327/401 Graa40150-350 Salvador, BAE-mail: [email protected]

Sociedade Brasileira de Anestesiologia, 2008


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Revista Brasileira de Anestesiologia 493Vol. 58, No 5, Setembro-Outubro, 2008

DOR NEUROPTICA ASPECTOS NEUROQUMICOS

HIPERALGESIA SECUNDRIA E SENSIBILIZAO CENTRAL

Hiperalgesia secundria decorrente do comprometimen-to de tecidos neurais e no-neurais adjacentes leso pri-mria e est associada sensibilizao central. Assim,pacientes com dor neuroptica podem sentir alodinia me-

cnica na pele, relacionada com a transmisso nervosa porfibras A. Isso porque o estmulo nocivo proveniente de fi-bras A ao alcanar o corno dorsal da medula espinal (l-mina I) pode ativar as clulas de variao dinmica ampla(lmina V) e aumentar a eficcia sinptica das fibras A.Assim, a perda da funo tctil em pacientes com dor neu-roptica pode provocar o desaparecimento da alodinia 4.

Papel dos Aferentes PrimriosO fato de receptores que se expressam predominantementenas fibras nervosas de pequeno dimetro, como os cana-biides e fatores neurotrficos, quando estimulados rever-terem a hiperalgesia trmica e mecnica aps SNL,fortalece a hiptese de que dor neuroptica est relaciona-da com o trauma do aferente primrio 5,6.

Hiptese do Aferente Primrio LesadoNa leso do aferente primrio est bem documentado queh atividade espontnea e ectpica a estmulos trmicos,qumicos e mecnicos do neuroma traumtico 7. Leso defibras distais ao gnglio da raiz dorsal provoca degeneraovaleriana no local, associada a fenmenos inflamatrios eativao de macrfagos, facilitando descargas eltricasanormais de regies no comprometidas pela leso. Ocorre,ento, aumento da expresso de receptores TRVP1 (recep-

tor potencial transitrio vanilide tipo I), fatores neurotrficosderivados do encfalo (BDNF) e neurotransmissores exci-tatrios, como o peptdeo relacionado com o gene da cal-citonina (CGRP). As fibras C adjacentes e intactas, ento,por pertencerem a um mesmo nervo ou fascculo das lesa-das, desenvolvem aumento de sensibilidade a catecola-minas e da expresso de canais de sdio Nav 1.8. Issopoderia explicar por que a rizotomia de L4 pode aliviar a hi-peralgesia mecnica decorrente da leso de L5 em ratos

2,3.Tambm, a injeo de anestsico local direto no gnglio daraiz dorsal de L5 em ratos submetidos ao modelo SNL re-verteu alteraes decorrentes da dor neuroptica 8. Isso

apesar da leso de L5 provocar atividade neuronal espon-tnea preferencial em fibras A. Esse fato sugere que a ati-vidade espontnea da fibra A inicia a sensibilizao centrale altera a expresso fenotpica do aferente primrio (fibrasC). Uma nova expresso de neuropeptdeos normalmenterelacionados com fibras C pode ocorrer, assim como au-mento da atividade espontnea de fibras A2,3.

Hiptese do Aferente Primrio IntactoAps leso do nervo perifrico, atividade neuronal espont-nea se desenvolve em aferentes primrios que dividem amesma inervao com fibras seccionadas. A incidncia de

atividade neuronal espontnea alta e em torno de 50%.Contudo, a leso de nervo espinal em roedores provoca, emnervos intactos, sensibilidade aumentada adrenalina e aofator de necrose tumoral (TNF )9. H aumento da respostaao calor e ao frio decorrente da maior expresso de prote-nas para receptores potenciais transitrios (TRPV1) e ca-

nais sensveis ao frio (TRPA1) no corno dorsal da medulaespinal 10. Tambm existe aumento da expresso de cidoribonuclico mensageiro (RNAm) para o gene relacionadocom o peptdeo da calcitonina (CGRP), fator neurotrfico deri-vado do encfalo (BDNF) e receptores purinrgicos (P2X3) 2,3.

Dor Mediada pelo Sistema Nervoso SimpticoA influncia do sistema nervoso simptico em quadros dedor neuroptica muito relevante. Sndrome complexa regio-nal quadro clnico que se manifesta normalmente com dorintensa em extremidade. Os pacientes apresentam edema,hiperalgesia ou alterao motora que pode melhorar com oemprego de bloqueio simptico ou de antagonistas de re-ceptores -adrenrgicos, indicando um componente simp-tico. Em modelos animais de dor neuroptica de SNL nonvel de L6, mais de 60% dos nociceptores intactos exibematividade espontnea e mais de 50% respondem a agonis-tas -adrenrgicos 2,3.

Canais de SdioOs canais de sdio Nav 1.3, 1.7, 1.8 e 1.9 so encontradosno gnglio da raiz dorsal e esto envolvidos na gerao depotencial de ao e conduo de nociceptores. Os Nav 1.3e 1.7 so sensveis a tetrodoxina e os outros dois insens-veis. H um aumento da expresso de Nav 1.3 no gnglio

da raiz dorsal de axnios lesados. Esse canal possui pro-priedades cinticas que facilitam a descarga repetitiva. Asubunidade 2 regula a abertura do canal, e ratos que noexpressam essa subunidade no desenvolvem hiperalge-sia mecnica aps leso de nervo. Assim, a grande densi-dade de canais de sdio voltagem dependente no nervolesado, pode fazer com que a despolarizao neuronal duremais tempo que o perodo refratrio dos canais de sdioadjacentes, permitindo que o potencial de ao se propaguede forma antidrmica (de proximal para distal) nos nervos. Asfreqncias de pulsos rpidos em fibras de grosso calibrepodem levar sensibilizao central, pois podem estimular

fibras nociceptivas adjacentes. Mutaes em canais de s-dio tipo Nav 1.7 podem provocar reduo da excitabilidadedo sistema nervoso simptico e hiperexcitabilidade de fibrasde pequeno calibre. Isso explicaria o quadro de edema, ver-melhido e dor da eritromelalgia 11.

Papel da Sensibilizao CentralA sensibilizao central envolve mecanismos homossinp-ticos e heterossinpticos. A sensibilizao homossinpticasignifica que o estmulo-teste e o condicionante esto as-sociados ao mesmo aferente. Isso pode ser exemplificadono fenmeno de wind up, quando estmulos contnuos e de


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KRAYCHETE, GOZZANI E KRAYCHETE

baixa freqncia de estimulao de aferentes de fibras Cprovocam aumento da resposta de clulas especficas docorno dorsal da medula espinal. Na sensibilizao hete-rossinptica o estmulo teste e o condicionante se relacio-nam com diferentes aferentes. Nesse caso, os impulsosnocivos aumentam a eficcia sinptica de mecanorecep-

tores ligados a fibras A. Assim, na dor neuroptica ocorresensibilizao homo- e heterossinptica demonstrada emmodelos de leso L5 pela tcnica SNL. As fibras mielini-zadas (A e A) de L5 desenvolvem atividade espontnea.O impulso dessas fibras pode levar a sensibilizao ho-mossinptica no trato espinotalmico justificando dor cr-nica persistente. Por outro lado, pode haver projeo parao segmento adjacente no nvel de L4, com sensibilizaoheterossinptica. Assim, ao aplicar-se estmulo mecnicoem fibras A? na pele correspondente ao trajeto de L4, podehaver sensibilizao de aferentes de fibras nas clulas re-lacionadas com L4 no corno dorsal da medula espinal. Os

aferentes intactos de L4, ento, apresentam hiperalgesiamecnica e trmica 2,3.A sensibilizao central ocorre ou por aumento da eficciasinptica ou por liberao excessiva de neurotransmisso-res excitatrios.

Alteraes Pr-SinpticasA liberao de glutamato inibida por ativao de recepto-res gabargicos (tipo B), para adenosina e para opiides(tipo ) 12. A reduo ou a falha da funo desses recepto-res podem levar a hiperexcitabilidade neuronal do nervo le-sado. Tambm, pode haver aumento das subunidades de

canais de clcio tipo 2 no gnglio da raiz dorsal e na me-dula espinal 13, fato que provoca a liberao de neurotrans-missores excitatrios. A alterao fenotpica de fibras A nador neuroptica causaria, de maneira semelhante, a libera-o pr-sinptica de substncia P facilitando a sensibiliza-o do corno dorsal da medula espinal.

Alteraes Ps-SinpticasA liberao de substncia P e CGRP alm de outros neu-rotransmissores excitatrios (aspartato e glutamato) nafenda sinptica causa ativao de receptores NMDA (N-metil-D-aspartato) e AMPA (Aminohidroximetilisoxasolepropinico)com aumento da entrada de clcio na clula, formao docomplexo clcio-calmodulina, ativao da enzima clcio-calmodulina cinase II e das vias neuronais do xido ntricosintetase, com formao de xido ntrico. Isso promove aoespecfica de cinases de protenas (A e C), de cinases deprotenas ativadas por mitgeno (ERK , JNK p38, MAPK)e de fatores transcricionais CREB, ATF-2 (Protena elemen-to-ligao para resposta) que ao serem fosforilados se li-gam a promotores de c-fos e de c-jun (genes de formaoimediata), resultando na sntese de produtos gnicos nu-cleares que se dimerizam para formar o complexo AP-1 evrios outros genes que facilitam a excitabilidade neuronal

e alteraes da neuroplasticidade no corno dorsal da me-dula espinal 14. possvel que no nervo lesado haja um au-mento da expresso de RNAm para receptores AMPA eNMDA no corno dorsal da medula espinal. A transcriognica parece que est mais vinculada ativao de recep-tores NMDA e neurocinina (NK1), alm da ao do xido

ntrico em nveis pr- e ps-sinptico14

.Por outro lado, aps a leso do nervo pode existir reduoda expresso de receptores inibitrios e a sensibilizaoneuronal provavelmente ser decorrente de mecanismosfacilitadores. Depresso de longa durao um fenmenooposto a potencializao de longa durao que ocorre emclulas inibitrias tipo gaba no corno dorsal da medulaespinal e levaria a sensibilizao neuronal. Pode haver re-duo da expresso de canais de potssio e aumento decanais de cloro que, se abertos, poderiam inibir neurniosgabargicos, levando excitao nervosa. Tambm, h apossibilidade de apoptose de neurnios gabargicos ou

perda de neurnios que contm glicina em modelos expe-rimentais para dor neuroptica, implicando facilitao daconduo nervosa 2,3.

CLULAS E DOR NEUROPTICA

MastcitosOs mastcitos esto presentes no nervo perifrico e podemser ativados aps o aumento, no local da leso, de adeno-sina ou bradicinina 15. Isso causa a liberao de grnuloscontendo histamina, proteases (triptases e receptores PAR-2), citocinas e fatores neurotrficos (NGF) capazes de: exci-tarem diretamente os nociceptores e as clulas do gnglioda raiz dorsal; facilitarem a ao de SP e CGRP; e provoca-rem dor espontnea em queimao 16. Tambm, pode haversntese, transcrio, translao e secreo de prostaglan-dinas, citocinas e quimiocinas 17, para o local da leso nervo-sa, alm de recrutamento de leuccitos incluindo neutrfilose macrfagos com ao indireta no sistema nervoso neuro-vegetativo 18.

NeutrfilosOs neutrfilos aderem ao endotlio vascular e migram pararea inflamatria do nervo lesado, liberando lipoxigenasese citocinas que atuam diretamente no receptor para dor. As-

sim, a depleo de neutrfilos circulantes antes da lesoexperimental de nervos atenua a hiperalgesia 19. Os neutr-filos liberam quimiocinas e defensinas que promovemquimiotaxia para macrfagos e linfcitos. Por outro lado, osmacrfagos fagocitam neurnios e clulas de Schwann de-generados ou mortos e residem no sistema nervoso cen-tral e perifrico 20. Os macrfagos liberam prostaglandinas,citocinas (interleucina 6 IL-6, TNF, interleucina 1 IL-1) e radicais superxidos que esto implicados na dorneuroptica, tanto que a depleo de macrfagos em ratoscom nervos lesados reduz a hiperalgesia 21.


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LinfcitosOs linfcitos responsveis pela imunidade celular (T) soencontrados no local da leso em modelos de dor neuro-ptica, expressando-se na periferia e no sistema nervosocentral. Assim, ratos sem clulas T desenvolvem menosalodinia mecnica e hiperalgesia trmica quando submeti-

dos leso de nervo isquitico22

.Os linfcitos T podem ser divididos em clulas CD4+ (helper)e CD8+ (citotxica) que provocam reaes especficas, TH1e TH2, respectivamente, conforme a secreo de citocinas.A resposta TH1 libera interferon-gama e IL-2 e est envolvi-da nas respostas inflamatrias moduladas por clulas e aresposta TH-2 (IL-4, IL-5, IL-6, IL-9 e IL-10) est envolvida naresposta alrgica com produo de anticorpos e inibio dasntese de citocinas pr-inflamatrias 23. possvel que es-sas respostas possuam efeitos opostos na evoluo da dorneuroptica, haja vista que a transferncia de linfcitos CD4+

aumenta a resposta ao estmulo doloroso em ratos e a declulas CD8+ reduz a sensibilidade dor 22.

Clulas da GliaAs clulas da glia e as de Schwann interagem com os neu-rnios promovendo manuteno da homeostase, regulan-do as concentraes de neurotransmissores, de ons e o pHdo extracelular. Na dor neuroptica, a microglia parece de-sempenhar papel fundamental no incio da leso e os as-trcitos na manuteno 24. A microglia ativada por vriosneuromediadores tipo ATP, bradicinina, substncia P, frac-talcina, Toll-like receptor4 (TLR4)

25,26. O ATP ativa recepto-res P2X4 no sistema nervoso central; a fractalcina umaquimiocina expressa na superfcie dos neurnios espinais

que ativa o receptor CX3CR1 na microglia e os receptoresTLR4 reconhecem molculas de estruturas variadas libera-das durante a leso nervosa. No se sabe, contudo, como,aps ativao da microglia, ocorre a dor neuroptica. pro-vvel que as clulas da glia liberem vrios neurotransmis-sores excitatrios, como a prostaglandina, o xido ntrico, ascitocinas e as quimiocinas, ativando diretamente o aferentesensitivo. Tambm pode haver ativao do lado contralateraldo corpo, por propagao de ondas de clcio por entre asjunes neurais, facil itando a liberao de neuromediado-res excitatrios 27.Por outro lado, as clulas de Schwann interagem com as

clulas T expressando molculas de histocompatibilidadeMHC classe II 28. As clulas de Schwann secretam citocinas(IL-6, IL-1, TNF), fatores neurotrficos (NGF), prostaglandi-nas E2 e ATP 29. Tambm expressam canais inicos e re-ceptores para glutamato e citocinas 30. Assim, provvel quecontribuam na gnese da dor neuroptica.

NEUROMEDIADORES

BradicininaA bradicinina e a calidina so formadas no sangue e nos te-cidos. A bradicinina age em receptores B1 e B2, sensibiliza

nociceptores perifricos (desinibindo receptores vanilides TRPV1), potencializa a transmisso sinptica para gluta-mato na medula espinal 31, estimula macrfagos a liberarcitocinas, secreta fatores quimiotticos para neutrfilos emoncitos e facilita a liberao de histamina dos mast-citos. A leso do nervo isquitico em ratos aumenta a ex-

presso de receptores B2 e B1 no gnglio da raiz dorsal eh predominncia de receptores B1 no corpo celular dosaxnios mielinizados. Esse fato sugere que o receptor B2esteja envolvido na sensibilizao central 31.

ATP e AdenosinaO ATP um neurotransmissor clssico, mas tambm li-berado por clulas no-neuronais e tecido lesado. Age emreceptores purinrgicos (P1 ou P2). Os receptores P2 po-dem ser subdivididos em P2 X e P2 Y que so acoplados,respectivamente, protena G e aos canais inicos 32.Em modelos experimentais para dor neuroptica, h redu-o (aps axotomia ou ligadura parcial do nervo) ou aumen-to (leso constritiva crnica) de receptores P2X3; contudo,mesmo na reduo, h aumento da sensibilidade dessesreceptores. De modo que o bloqueio de receptores P2X3atenua a alodinia trmica e mecnica em ratos 33. Os recep-tores P2X4 tambm aumentam sua expresso na microgliaaps a leso de nervo e o bloqueio farmacolgico do P2X4reverte a alodinia 34. Os receptores P2X7 esto presentes nasclulas T e macrfagos. Ratos que no expressam esse re-ceptor no apresentam dor neuroptica 35. Por outro lado, osreceptores P2Y1 aumentam em 70% aps leso do isqui-tico em ratos 36.

SerotoninaA serotonina um neurotransmissor sintetizado e liberadopor neurnios do sistema nervoso central (gnglio da raizdorsal, citoplasma e clulas de Schwann). Na periferia, aserotonina liberada pelas plaquetas e induz hiperalgesiapor ao direta no aferente primrio via receptor 5HT1A

37. Naleso parcial do nervo em ratos, a serotonina contribui paraa hiperalgesia mecnica via receptores 5HT2A e 5HT3

38.

EicosanidesOs metablitos do cido araquidnico incluem as prosta-glandinas, os tromboxanos e os leucotrienos. As prosta-glandinas PGE

2

e PGI2

agem em receptores acoplados aprotena G (EP 1-4; IP, respectivamente) induzem hiperalgesiade nociceptores 39 perifricos e no sistema nervoso central 40.Em modelos de dor neuroptica h aumento da expressode cicloxigenases (COX-2) na regio da leso, na medula es-pinal (COX2 e COX1) e no tlamo, associado ao aumento demacrfagos e maior produo de PGE2 em mastcitos

41,42.Esse fenmeno est relacionado com a ao de IL1, TNF,fator de crescimento nervoso (NGF), MCP-1 (protena qui-miotxica para moncitos) e radicais superxidos (ROS).Assim, as PGE2 podem despolarizar diretamente as clu-las de variao dinmica ampla no corno dorsal da medula


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espinal, ativar canais de sdio tetrodoxina resistente e declcio voltagem dependente, inibir canais de potssio e au-mentar a liberao de glutamato, substncia P ou CGRP oubloquear a inibio da glicina sobre os neurnios nocivosespecficos. Tambm, o tratamento com PGE2 de cultura deneurnios do corno dorsal da medula espinal aumenta a

expresso de receptores NK1 para substncia P, alm daPGE2 induzir em modelos de leso de nervo a maior expres-so de fator bsico de crescimento de fibroblastos (bFGF),de fator de crescimento nervoso, de xido ntrico sintetase(NOS), de canais de sdio Nav 1.7 e Nav 1.8, de receptoresTRPV1 (receptores vanilides transitrios) e de metalopro-teinases (MMPs) envolvidos na degenerao axonal, naperda da bainha de mielina, no recrutamento de leuccitose macrfagos para o local da leso e na quebra da barreirahematoenceflica no sistema nervoso central. Esses fatorescontribuem na manuteno da dor crnica persistente 43.Apesar de haver reverso da hiperalgesia trmica e mec-nica aps a injeo subcutnea de antiinflamatrios 38 emanimais de experimentao, em humanos, os antiinflama-trios so ineficazes na prtica clnica em se tratando de dorneuroptica.Por outro lado, o leucotrieno B4 (LTB4) produz hiperalgesia li-berando mediadores de neutrfilos 44. Tambm os fatoresneurotrficos (NGF) produzem hiperalgesia por induzir a li-berao de LTB4 dos mastcitos e aumentar o recrutamen-to de neutrfilos 45.

CitocinasAs citocinas so pequenas protenas intermedirias deinteraes entre clulas em pequenas distncias. A IL1, a

IL-6 e o TNF so pr-inflamatrias e induzem a produode cada uma de forma seqencial e possuem ao sinr-gica 46. Tambm, a administrao exgena dessas substn-cias induz dor e hiperalgesia 47. A ligao da IL1 ao receptorIL1-RI inicia uma srie de eventos intracelulares, ativandofatores transcricionais, induzindo a expresso de COX-2,xido ntrico sintetase e IL1, a IL-6 e o TNF. Assim, a IL1exerce ao direta e indireta nos nociceptores 48 e h au-mento da sntese de IL1 na leso de nervo perifrico 49, demodo que em camundongos h alvio da dor neuropticacom empregos de anticorpos para o receptor de IL-1.A IL-6 sintetizada pelos mastcitos, moncitos, linfcitos,

neurnios e clulas da glia. A leso do nervo isquitico pro-move aumento da expresso de IL-6 no local, assim comono corno dorsal da medula espinal e no gnglio da raizdorsal 50. Se injetada nos ventrculos laterais de ratos, a IL-6induz hiperalgesia trmica 51. Apesar de estudos controver-sos, em ratos que no produzem IL-6 h um retardo no de-senvolvimento de alodinia mecnica aps leso de nervoperifrico 52.O TNF-, aps agir em receptores especficos, ativa fatorestranscricionais (p38 MAPK e NF) e libera fatores depen-dentes de COX-2. A injeo intraplantar de TNF em roedoresinduz hiperalgesia mecnica 53 e aps a aplicao tpica e

intraneural ocorre hiperalgesia trmica e alodinia mecni-ca 54. A leso do aferente primrio provoca aumento deTNF no corno dorsal da medula espinal, locus ceruleusehipocampo 55.

Neurotrofinas

As neurotrofinas so protenas dimricas sintetizadas e li-beradas por vrias clulas imunes (mastcitos e linfcitos)e essenciais para o desenvolvimento normal do sistemanervoso dos vertebrados 56. A famlia inclui o fator de cresci-mento nervoso (NGF), fator neurotrfico derivado do enc-falo (BDNF), neurotrofina 3 e neurotrofina 4/5. Outra protenacom propriedades neurotrficas no-dimricas o fatorneurotrfico derivado da glia (GDNF).As neurotrofinas agem em receptores especficos as tiro-sinas cinases (TrK) A para o NGF, B para o BNDF e NT-4/5e C para as NT-3 e possuem maior expresso na vida em-brionria 57.A leso do nervo induz modificaes na expresso de fato-res de crescimento. A mudana ocorre no tecido sem iner-vao, na clula de Schwann, no corno dorsal da medulaespinal e no gnglio da raiz dorsal. Aps a leso nervosa,entretanto, a sntese dessas substncias, assim como ados receptores, aumenta 58. H elevao do fator neurotr-fico (NGF) em territrio inervado por L4 na leso experimen-tal SNL em L5, com transporte retrgrado de neurotrofinaspara o gnglio da raiz dorsal, alterando a expresso de fa-tores neurotrficos derivados do encfalo (BDNF). Assim, huma influncia de fatores neurotrficos em axnios lesadose nos intactos. Os fatores neurotrficos (NGF) aumentam aexpresso de canais relacionados com a transduo de est-

mulo mecnico (TRPV4). Assim, hiperalgesia ao frio pode serdecorrente da expresso anormal de canais, como TRPA1e TRPM8. Os NGF, alm de sensibilizarem diretamente osnociceptores na periferia, atuam em clulas do sistemainume e simptico 59, enquanto o BDNF facilita a excitaodos neurnios do corno dorsal da medula espinal 60. A ex-presso dessas substncias aumenta, em modelos expe-rimentais, na regio relacionada com a leso do nervo porconstrio, assim como no gnglio da raiz dorsal correspon-dente61. Tambm, a injeo endoneural de fator neurotrficoprovoca brotamentos de sinapses e sinais de hiperalgesiatrmica, enquanto a administrao perineural dessa subs-tncia determina o aparecimento de hiperalgesia mecnica.Os fatores de crescimento possuem papel fundamental nodesenvolvimento e manuteno dos neurnios de pequenocalibre e do sistema nervoso simptico. Nos axnios in-tactos leso, h aumento de receptores adrenrgico nocorpo celular, com conseqente sensibilidade desses ner-vos adrenalina circulante. Em modelos animais, bloqueiocom anestsico local de fibras lesadas reduz muito a suaatividade espontnea e os brotamentos nervosos do siste-ma nervoso simptico por at cinco semanas aps a leso,havendo bloqueio da produo de NGF via inibio da tiro-sina cinase 2,3.

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xido Ntrico e Radicais SuperxidoOs radicais superxido so liberados por mastcitos e c-lulas da glia (astrcitos e microglia). O xido ntrico, por suavez, possui as formas endotelial e neuronal que so cons-titutivas, enquanto a induzida se expressa nas clulas dosistema imune. O xido ntrico provoca hiperalgesia aps

injeo na pele e articulaes62

e est implicado na sen-sibilizao central 48, fortalecendo a ao da PG2 em mode-los de dor neuroptica 63.

cido LisofosfatdicoO cido lisofosfatdico (LPA) uma substncia derivada dometabolismo de lipdios que liberado aps a leso tissu-lar e pode estar envolvido na dor neuroptica. Os maioresprodutores de LPA so as plaquetas, sendo o soro a maiorfonte desse elemento. Os receptores para LPA (LPA1 a 4) es-to distribudos no sistema nervoso central e perifrico.Tambm esto acoplados protena G12/13 e, quando aci-

onados, ativam a GTPase RHoA e uma srie de segundosmensageiros, incluindo a cinase Rho ou ROCK. A injeointratecal de LPA em animais de experimentao provocaalodinia mecnica e hiperalgesia trmica. Ocorre uma redu-o drstica de protenas associadas mielina (protenamielnica bsica e perifrica, MPB e PMP 22, respectivamen-te) e aumento da expresso de fosfocinase C e canais declcio (Cav2-1) com degenerao do nervo, brotamento desinapses e aumento da excitabilidade neuronal 64.

DOR NEUROPTICA E DEGENERAO DO NERVO

Um dos primeiros eventos aps a leso do nervo o influ-xo de clcio. O clcio inicia a cicatrizao tissular agrupandovesculas do axolema ao redor das terminaes nervosasdistais e proximais lesadas. O aumento do clcio intrace-lular tambm ativa cinases de protenas dependentes declcio e outras proteases (UPS) que facilitam a liberao decitocinas e a destruio de microtbulos e microfilamentos,importantes no transporte axonal de substncias e no me-canismo da dor neuroptica. H, ento, acmulo no local deSP, CGRP, xido ntrico, fatores neurotrficos e canais desdio que juntos amplificam a excitabilidade neuronal 65.Apesar da leso perifrica da fibra nervosa tipo C provocarreduo no corno dorsal da medula espinal de SP, de neu-

rotrofinas (BDNF), de receptores (VR1 e P2X3), de canais declcio tipo N de alta voltagem, h regulao ascendente decanais TTX sensveis (TTXs) tipo III e h translocao docorpo celular para o neuroma de canais de sdio TTX resis-tentes (TTXr), facilitando o aumento da excitabilidade ner-vosa 66. Os canais TTXs tipo Nav 1.3, que tm caractersticacintica de fcil ativao e inativao, podem aumentar suaexpresso em torno de duas a 30 vezes em modelos deaxotomia do gnglio da raiz dorsal, da ligadura do nervo es-pinhal, da leso constritiva crnica, da leso difusa do ner-vo, da neuropatia diabtica e da ps-herptica 11.

Quando a fibra nervosa est intacta (inflamao), h aumen-to de neuromediadores excitatrios no corno dorsal da me-dula espinal e maior expresso de canais de sdio (TTXr),fato que facilita a hiperexcitabilidade neuronal e dificulta aresposta ao tratamento com anestsicos locais 66.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-bras C (lmina II), ampliando o campo receptivo do neurnioe facilitando a interpretao de estmulos mecnicos perif-ricos incuos como agressivos 67. Isso explica, por exemplo,a alodinia mecnica que acontece na neuralgia ps-herp-tica 68. 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 69. Alm disso, pode existir algumadesproporo entre as vias excitatrias e as de supresso

da dor, com reduo da atividade inibitria da glicina, daGABA e dos opiides 66.

ASPECTOS CENTRAIS

Em modelos de dor neuroptica em animais de experimen-tao, o efeito inibitrio de fibras descendentes provenien-tes da substncia periaquedutal cinzenta do locus coeruleusest reduzido em 50% em relao ao normal. H eficciareduzida do sistema opiide na medula espinal, com dimi-nuio de -endorfinas no encfalo e na medula espinal econseqente reduo do efeito analgsico da morfina, tanto

por via sistmica como por via espinal. Isso sugere que osreceptores para opiides ou outros fatores necessrios paraativao do sistema opiide espinal estejam comprometidosaps a leso do nervo 2,3. Por outro lado, em neurnios do cor-no dorsal da medula espinal que expressam c-junpode haverinduo de morte celular programada. Isso envolve estudoscom a famlia de genes Bcl-2 e Bax que inibem e favorecema morte celular, respectivamente. Em ratos com nervo sec-cionado e que aumentam a expresso de c-jun, h reduoda relao Bcl-2/ Bax, indicando tendncia a apoptose edesaferentao dos neurnios espinais ps-sinptico 14.A destruio do cordo posterior ou do ncleo gracilisipsi-lateral leso nervosa pode abolir a alodinia mecnica emratos. Por outro lado, a alodinia tambm pode ser inibidapela destruio seletiva de vias descendentes do troncoenceflico no cordo dorsolateral, indicando que h umaparticipao das vias ascendentes e descendentes nas al-teraes decorrentes da dor neuroptica. A alodinia trmicapode ser abolida pela injeo de lidocana ou de antagonis-tas de receptores para colecistocinina (CCK) na regio ven-tromedial do bulbo (ncleo da rafe magnus). Quando hleso de nervo possvel que ocorra fenmeno de facilitaodescendente envolvendo o ncleo da rafe medial no bulbo(NRM) e a CCK. Tanto que a seco de fibras descenden-



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tes pode reduzir consideravelmente a alodinia mecnica outrmica em animais de experimentao. Tambm, os im-pulsos bulboespinais so capazes de ativar neurnios sim-pticos ps-sinpticos que contribuem para manuteno dador neuroptica 2,3,14.Com relao aos aspectos neurofisiolgicos da dor neuro-

ptica na SNL, h aumento da atividade neuronal espont-nea de regies talmicas somatossensoriais (ncleo ventralposteromediano, VPM; e lateral, VPL) que podem ser inibi-das por substncias que bloqueiam a expresso de canaisde sdio Nav 1.3. Por outro lado, a imagem funcional do t-lamo contralateral dor neuroptica revela metabolismodiminudo. No crtex cerebral, 10% dos neurnios se com-portam de maneira semelhante aos talmicos, sobretudoos localizados na borda da zona desaferentada do crtexsomestsico primrio. H aumento da freqncia teta (4 a7 Hz) no eletroencefalograma e elevao do metabolismo oudo dbito cortical nas regies insular, parietal posterior, pr-frontal e cingular. O oposto acontece no crtex cingular me-

diano (rea 24 de Brodmann) e anterior e perigenual (reas32 e 25 de Brodmann). Alguns pesquisadores demonstra-ram que o aumento do dbito perigenual aps estimulaocortical motora do gnglio de Gasser reduziu a intensidadeda dor. Isso pode fortalecer a hiptese da relao entre alte-raes perigenuais e falha do controle inibitrio descenden-te. H tambm reduo, por internalizao, de receptorespara opiides na substncia cinzenta periaquedutal, no t-lamo mediano, crtex pr-frontal e nsula. Essa reduo bilateral e simtrica na leso perifrica e assimtrica e pre-ponderante no lado ipsilateral quando a leso central 2.

CONCLUSO

A dor neuroptica ainda um desafio para os pesquisado-res clnicos e experimentais. Os mecanismos, complexos eno completamente elucidados, desenvolvem dinmicacom resultados, por vezes, contraditrios. Entender a neu-robiologia da dor neuroptica um passo para melhoria dosresultados no tratamento dessa sndrome. Essa compreen-so poder resultar na elaborao de frmacos que visema alvos especficos e que proporcionem respostas eficazes.

Neuropathic Pain NeurochemicalAspects

Durval Campos Kraychete, TSA, M.D.; Judymara LauziGozzani, TSA, M.D.; Angiolina Campos Kraychete, M.D.

INTRODUCTION

Neuropathic pain is defined as pain secondary to nerve da-mage or dysfunction and, more widely, as a consequence ofdamage or disease of the somesthetic system 1. It is a com-

plex syndrome whose biological mechanisms are not clear,involving inflammatory and immunologic theories.

EXPERIMENTAL MODELS FOR THE STUDY OFNEUROPATHIC PAIN

Most experimental models described in the literature involvemice and were developed from traumatic, metabolic, or toxicperipheral lesions:1. Spinal nerve ligature (SNL) one or more spinal nerves

innervating the paw are ligated and cut.2. Partial sciatic ligature (PSL) part of the sciatic nerve is

ligated.3. Chronic Constrictive Injury (CCI) includes the placement

of four ligatures on the sciatic nerve tightened by a chromesuture.

4. Spared nerve injury (SNI) fibular and posterior tibialnerves are severed and the sural nerve is spared. Thistechnique causes long-term behavioral changes.

Other methods include the intraperitoneal injection of strep-tozocin to mimic diabetic neuropathy, or paclitaxel and vin-cristine for chemotherapy induced neuropathy. Models ofcentral pain use contusion (trauma using the force of impactof tissue dislocation), or ischemic lesions from slow com-pression by clamping or balloon insufflation. Cytotoxic me-thods use injections of glutamate analogues (cainate) orsubstances that cause lesion in specific areas of the graymatter. The techniques described are aimed at causing me-chanical and thermal hyperalgesia 2,3.

SECONDARY HYPERALGESIA AND CENTRAL SENSITIZATION

Secondary hyperalgesia is due to damage of neural and non-neural tissues adjacent to the primary lesion, and it is as-sociated with central sensitization. Thus, patients withneuropathic pain can feel mechanical allodynia on the skinrelated to nerve transmission through A fibers. This occursbecause when the noxious stimulus from A fibers reachesthe dorsal horn of the spinal cord (lamina I), it can activatewide dynamic range neurons (lamina V) and increase thesynaptic efficacy of A fibers. Therefore, the loss of tactilefunction in patients with neuropathic pain can lead to an endof the allodynia 4.

Role of Primary AfferentsSince receptors that are expressed predominantly in small-diameter nerve fibers, such as cannabinoid and neutrotro-phic receptors reverse thermal and mechanical hyperalgesiaafter SNL when they are stimulated, this reinforces the hy-pothesis that neuropathic pain is related to trauma of theprimary afferent 5,6.

Hypothesis of the Damaged Primary AfferentIn the lesion of the primary afferent, it has been widely do-cumented that there is spontaneous and ectopic activity ofthe traumatic neuroma to thermal, chemical, and mechanical

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stimulus 7. Damage of fibers distal to the dorsal root ganglioncauses local valerian degeneration associated with inflam-matory phenomena and activation of macrophages, facili-tating abnormal electric discharges from areas not affectedby the lesion. An increase in the expression of TRVP1 re-ceptors (transient receptor potential vanilloid-1), brain derived

neurotrophic factors (BDNF), and excitatory neurotransmit-ters, such as the calcitonin gene-related peptide (CGRP) isseen. Since adjacent intact C fibers belong to the samedamaged nerve or fasciculus, they develop an increasedsensitivity to catecholamines and in the expression of Nav1.8 sodium channel receptors. This could explain why L4 rhi-zotomy can alleviate the mechanical hyperalgesia secondaryto the L5 lesion in mice

2,3. The injection of a local anestheticdirectly in the L5 dorsal root ganglion in the model of SNL inmice reversed the changes secondary to neuropathic pain 8.This occurred despite the fact that the L5 lesion causes spon-taneous neuronal activity preferentially in A fibers, whichsuggests that the spontaneous activity of the A fiber initia-tes the central sensitization and changes the phenotypic ex-pression of the primary afferent (C fibers). A new expressionof neuropeptides normally related with C fibers can occur, aswell as an increase in the spontaneous activity of A fibers 2,3.

Hypothesis of the Intact Primary AfferentAfter damage of a peripheral nerve, spontaneous neural acti-vity develops in primary afferents that share the sameinnervation with the severed nerves. The incidence of spon-taneous neuronal activity is high, around 50%. However, thedamage of a spinal nerve in rodents leads in intact nervesto an increased sensitivity to adrenaline and tumor necrosis

factor (TNF) 9. There is an increase in the response to heatand cold secondary to the increased expression of proteinsfor transitory receptor potential vanilloid (TRVP1) and cold-sensitive channels (TRPA1) in the dorsal horn of the spinalcord 10. There is also an increased expression of messengerribonucleic acid (mRNA) for the calcitonin gene-relatedpeptide (CGRP), brain-derived neurotrophic factor (BDNF),and purinergic receptors (P2X3) 2,3.

Pain Mediated by the Sympathetic Nervous SystemThe influence of the sympathetic nervous system on neu-ropathic pain is very relevant. Complex regional syndrome

usually manifests itself with severe pain in one extremity.Patients present with edema, hyperalgesia, or changes inmotor function, which might improve with a sympathetic blockor with -adrenergic receptors antagonists, indicating a sym-pathetic component. In animal models of neuropathic painsecondary to SNL at the level of L6, more than 60% of theintact nociceptors show spontaneous activity and more than50% respond to -adrenergic agonists 2,3.

Sodium ChannelsNav 1.3, 1.7, 1.8, and 1.9 sodium channels can be found inthe dorsal root ganglion and are involved in the generation

of action potentials and conduction of nociceptors. Nav 1.3and 1.7 are sensitive to tetrodotoxin and the other two are not.There is an increase in the expression of Nav 1.3 in the dor-sal root ganglion of damaged axons. This channel haskinetic properties that facilitate repetitive discharges. The 2subunit regulates the opening of the channel and mice that

do not express this subunit do not develop mechanical hy-peralgesia after nerve damage. Therefore, the high density ofvoltage-dependent sodium channels in the damaged nervecan cause neuronal depolarization to last longer than therefractory period of adjacent sodium channels, allowing theantidromic propagation of the action potential (from proximalto distal) in the nerves. The frequency of fast pulses in large-caliber fibers can lead to central sensitization because theycan stimulate adjacent nociceptive fibers. Mutations in Nav1.7 sodium channels can reduce the excitability of the sym-pathetic nervous system and cause hyperexcitability insmall-caliber fibers. This would explain the edema, erythe-ma, and pain of erythromelalgia 11.

Role of Central SensitizationCentral sensitization involves homo- and heterosynaptic me-chanisms. In homosynaptic sensitization, the test stimulusand conditioning are associated with the same afferent. Thiscan be exemplified by the wind upphenomenon, when thecontinuous low-frequency stimulation of afferent C fibers cau-ses an increase in the response of specific cells in the dor-sal horn of the spinal cord. In heterosynaptic sensitization,the test stimulus and conditioning are related in a differentway. In this case, nociceptive stimuli increase the synaptic effi-cacy of mechanoreceptors connected with A fibers. Thus,

neuropathic pain is accompanied by homo- and heterosynap-tic sensitization, which was demonstrated in models of L 5lesion using the SNL technique. L5 myelinated fibers (A andA) develop spontaneous activity. The impulse from thosefibers can lead to homosynaptic sensitization in the spino-thalamic tract, explaining the persistent chronic pain. On theother hand, projection to the adjacent segment at the L4level can lead to heterosynaptic sensitization. Therefore,when applying mechanical stimulus to A fibers in the skincorresponding to the L4 path, it can lead to sensitization ofafferent fibers in the cells related with L4 in the dorsal hornof the spinal cord. Thus intact L4 afferents show mechanical

and thermal hyperalgesia2,3

.Central sensitization occurs by an increase in synaptic effica-cy or due to excessive release of excitatory neurotransmitters.

Pre-Synaptic ChangesRelease of glutamate is inhibited by the activation of GA-BAergic (type B), adenosine, and opioid () 12 receptors. Thereduction or failure of the function of those receptors can leadto neuronal hyperexcitability in the damaged nerve. Calciumchannels 2 subunits in the dorsal root ganglion and in thespinal cord can also be increased 13, which cause the relea-se of excitatory neurotransmitters. The phenotypic change of

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A fibers in neuropathic pain would similarly cause the pre-synaptic release of substance P facilitating sensitization ofthe dorsal horn of the spinal cord.

Post-Synaptic ChangesThe release of substance P and CGRP, besides other exci-

tatory neurotransmitters (aspartate and glutamate) in thesynaptic cleft activates NMDA (N-methyl-D-aspartate) andAMPA (amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)receptors leading to an increase of calcium influx into thecell, formation of the calcium-calmodulin complex, activationof the enzyme calcium-calmodulin kinase II, and the neuro-nal pathways of nitric oxide synthase and production of nitricoxide. This promotes a specific action of protein kinases (Aand C), mitogen-activated protein kinases (ERK , JNK p38,MAPK), and the transcriptional factors CREB, ATF-2 (activa-ting transcription factor-2) that when phosphorylated bind toc-fos and c-jun (immediate-early genes) promoters, resultingin the synthesis of nuclear gene products that undergo di-merization to form the AP-1 complex and several other genesthat facilitate neuronal excitability and changes in the neu-roplasticity of the dorsal horn 14. It is possible that the dama-ged nerve shows increased expression of mRNA for AMPAand NMDA receptors in the dorsal horn of the spinal cord.Gene transcription seems to be connected more to the acti-vation of NMDA and neurokinin (NK1) receptors, besides thepre- and post-synaptic action of nitric oxide 14.On the other hand, a reduction in the expression of inhibitoryreceptors after nerve damage and neuronal sensitizationwould probably be secondary to facilitating mechanisms.Long-term depression is opposed to the long-term potentia-

tion that occurs in GABA type inhibitor cells in the dorsal hornof the spinal cord and would lead to neuronal sensitization.The expression of potassium and chloride channels can beincreased and if opened they could inhibit GABAergic neu-rons causing consequently nerve excitation. In experimentalmodels of neuropathic pain GABAergic neurons can alsoundergo apoptosis or glycine-containing neurons can be lostresulting in facilitation of the nerve conduction 2,3.

CELLS AND NEUROPATHIC PAIN

Mast CellsMast cells are present in peripheral nerves and can be acti-vated after the increase of adenosine or bradykinin in the siteof damage 15. This causes the release of granules containinghistamine, proteases (tryptases and PAR-2 receptors),cytokines, and neurotrophic factors (NGF) capable of: directexcitation of nociceptors and dorsal root ganglion cells; faci-litate the action of SP and CGRP; and provoke spontaneousburning pain 16. Synthesis, transcription, translation, and se-cretion of prostaglandins, cytokines, and chemokines 17 atthe site of nerve damage besides recruitment of leukocytesincluding neutrophils and macrophages that affect directlythe neurovegetative nervous system can also occur 18.

NeutrophilsNeutrophils adhere to the vascular endothelium and migrateto the site of inflammation in the damaged nerve releasing li-poxigenases and cytokines that affect pain receptors directly.Thus, depletion of circulating neutrophils before experimentalnerve lesion attenuates the resulting hyperalgesia 19. Neutro-

phils release chemokines and defensins that are chemo-tactic for macrophages and lymphocytes. On the other hand,macrophages that reside in the central and peripheral ner-vous systems phagocyte degenerated or dead neurons andSchwann cells 20. Macrophages release prostaglandins, cy-tokines (interleukin-6 IL-6, TNF, and interleukin 1 IL-1), and superoxide radicals -implicated on neuropathic pain,and the depletion of macrophages on mice with damagednerves reduces hyperalgesia 21.

LymphocytesLymphocytes responsible for cell-mediated immunity (Tcells) can be found on the damaged site in models of neu-ropathic pain, expressing themselves in the periphery and inthe central nervous system. Thus, mice that lack T cellsdevelop less mechanical allodynia and thermal hyperalgesiawhen subjected to damage of the sciatic nerve 22.T cells can be divided in CD4+ (helper) and CD8+ (cytotoxic),which provoke specific TH1 and TH2 reactions, respectively,according to the cytokines secreted. The TH1 response re-leases interferon-gamma and IL-2, and it is involved in cell-mediated inflammatory responses, while the TH2 response(IL-4, IL-5, IL-6, IL-9, and IL-10) is involved in the allergicresponse with the production of antibodies and inhibition ofthe synthesis of pro-inflammatory cytokines 23. Those res-

ponses could possibly have opposing effects in the evolutionof neuropathic pain, since the transference of CD4+ lympho-cytes increases the response to painful stimuli in mice, whilethe transference of CD8+ cells reduces hyperalgesia 22.

Glial CellsGlial and Schwann cells interact with neurons, promotingmaintenance of the homeostasis, regulating the concentra-tion of neurotransmitters and ions, and the extracellular pH.In neuropathic pain, microglial cells seem to play a funda-mental role in the beginning of the lesion and astrocytes inits maintenance 24. Microglia are activated by several neuro-mediators, such as ATP, bradykinin, substance P, fractalkine,and Toll-like receptor 4 (TLR4)

25,26. ATP activates P2X4 re-ceptors in the central nervous system; fractalkine is a che-mokine expressed on the surface of spinal neurons thatactivates the microglial CX3CR1 receptor, and TLR4 recep-tors recognize molecules of different structures releasedduring the nerve damage. However, it is not known howneuropathic pain develops after microglial activation. It ispossible that glial cells release several excitatory neuro-transmitters, such as prostaglandins, nitric oxide, cytokines,and chemokines, activating the sensitive afferent directly.Activation can also occur in the contralateral side of the body



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by propagation of calcium waves between neural junctions,facilitating the release of excitatory neuromediators 27.On the other hand, Schwann cells interact with T cells ex-pressing MHC class II molecules 28. Schwann cells secretecytokines (IL-6, IL-1, TNF), neurotrophic factors (NGF),prostaglandin E2, and ATP 29. They also express ion chan-

nels, and glutamate and cytokine receptors30

. Thus, it is pos-sible that they contribute to the genesis of neuropathic pain.

NEUROMEDIATORS

BradykininBradykinin and kalidine are formed in the blood and tissues.Bradykinin exerts its actions on B1 and B2 receptors, causessensitization of peripheral nociceptors (desinhibiting vanil-loid receptors TRVP1), potentiates glutaminergic synaptictransmission in the spinal cord 31, stimulates the release ofcytokines by macrophages, secretes neutrophil and mono-cyte chemotactic factors, and facilitates the release of his-tamine by mast cells. In mice, damage of the sciatic nerveincreases the expression of B2 and B1 receptors in the dor-sal root ganglion, with predominance of B1 receptors in thesoma of myelinated axons. This suggests that B2 receptorsare involved in central sensitization 31.

ATP and AdenosineATP is a classical neurotransmitter, but it is also released bydamaged non-neuronal cells and tissues. It exerts its actionsin purinergic receptors (P1 or P2). P2 receptors can be divi-ded in P2X and P2Y, which are coupled to protein G and ionchannels, respectively 32.

In experimental models of neuropathic pain P2X3 receptorsare reduced (after axotomy or partial nerve ligature) or in-creased (chronic constrictive lesion); however, even in theface of reduction those receptors show increased sensitivity.Blockade of P2X3 receptors attenuates thermal and mecha-nical allodynia in mice 33. The expression of P2X4 receptors isalso increased in microglia after nerve damage, and its phar-macological blockade reverses allodynia 34. P2X7 receptorscan be found in T cells and macrophages. Mice that do notexpress this receptor do not develop neuropathic pain 35. Onthe other side, P2Y1 receptors show a 70% increase afterdamage of the sciatic nerve in mice 36.

SerotoninSerotonin is a neurotransmitter synthesized and released bycentral nervous system (dorsal root ganglion, cytoplasm, andSchwann cells) neurons. In the periphery, serotonin is relea-sed by platelets and induces hyperalgesia by direct action inthe primary afferent via the 5HT1A receptors

37. In partial nervelesions in mice, serotonin contributes with mechanical hype-ralgesia through 5HT2A and 5HT3 receptors

38.

EicosanoidsArachidonic acid metabolites include prostaglandins, throm-boxanes, and leukotrienes. Prostaglandins PGE2 and PGI2

exert their action on protein G-coupled receptors (EP14 andIP, respectively) and induce hyperalgesia in peripheral 39 andcentral nervous system 40 nociceptors. The expression of cy-clooxygenase (COX-2) in the damaged area, in the spinalcord (COX2 and COX1), and in the thalamus is increased inmodels of neuropathic pain, associated with the increase in

the number of macrophages and in the production of PGE2 bymast cells 41,42. This phenomenon is related with the actionsof IL1, TNF, nerve growth factor (NGF), MCP-1 (monocytechemoattractant protein-1), and reactive oxygen species(ROS). Thus, PGE2 can depolarize directly cells with widedynamic range in the dorsal horn of the spinal cord, activatetetrodotoxin-resistant sodium channels and voltage-de-pendent calcium channels, inhibit potassium channels, andincrease the release of glutamate, substance P, or CGRP, orblock glycine inhibition on specific nociceptive neurons. Treat-ment of cultures of dorsal horn neurons with PGE2 increasesthe expression of substance P NK1 receptors, and in modelsof nerve lesions it induces greater expression of basic fibro-blast growth factor (bFGF), nerve growth factor, nitric oxidesynthase (NOS), Nav 1.7 and 1.8 sodium channels, TRVP1 re-ceptors (transitory receptor potential vanilloid-1), and metal-loproteinases (MMPs) involved in axonal degeneration, lossof myelin sheath, recruitment of leukocytes and macropha-ges to the site of damage, and disruption of the hematoen-cephalic barrier. Those factors contribute for the maintenanceof persistent chronic pain43. Despite the reversal of thermaland mechanical hyperalgesia after the subcutaneous injec-tion of anti-inflammatories 38 in laboratory animals, in hu-mans anti-inflammatories are ineffective in clinical practicefor the treatment of neuropathic pain.

On the other side, leukotriene B4 (LTB4) produces hyperalge-sia by releasing neuromediators from neutrophils 44. Be-sides, neurotrophic factors (NGF) also produce hyperalgesiaby inducing the release of LTB4 from mast cells, and increasethe recruitment of neutrophils 45.

CytokinesCytokines are small molecules that mediate the interactionsamong cells over distances. IL1, IL-6, and TNF are pro-inflammatory, induce the sequential production of each one,and are synergistic 46. The exogenous administration ofthose substances can also induce pain and hyperalgesia 47.

Binding of IL1 to the IL1-RI receptor triggers a series ofintracellular events activating transcriptional factors, inducingthe expression of COX-2, nitric oxide synthase, IL1, IL-6, andTNF. Thus, IL1 affects nociceptors direct and indirectly 48,in nerve damage its production is increased in peripheralnerves 49, and in mice the administration of antibodies for theIL-1 receptor alleviates neuropathic pain.Interleukin-6 is synthesized by mast cells, monocytes, lym-phocytes, neurons, and glia. Lesions of the sciatic nerve pro-mote the local increase in IL-6 expression, as well as in thedorsal horn of the spinal cord 50. In mice, the injection of IL-6in the lateral ventricles produces thermal hyperalgesia 51. Des-



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pite controversial studies, in mice that do not produce IL-6the development of mechanical allodynia after peripheralnerve lesion is delayed 52.After acting on specific receptors, TNF activates transcrip-tional factors (p36 MAPK and NF) and releases COX-2-dependent factors. The intraplantar injection of TNF in

rodents induces mechanical hyperalgesia 53 and after topicaland intraneural administration it induces thermal hyperalge-sia and mechanical allodynia 54. Lesion of the primary affe-rent leads to an increase in TNF in the dorsal horn of thespinal cord, locus ceruleus, and hippocampus 55.

NeurotrophinsNeurotrophins are dimeric proteins synthesized and releasedby several immune cells (mast cells and lymphocytes) andthey are essential for the normal development of the nervoussystem in vertebrates 56. This family includes nerve growthfactor (NGF), brain-derived neurotrophic factor (BDNF), and

neutrophin 3 and neutrophin 4/5. Glial cell-line derived neu-rotrophic factor (GDNF) is another protein with non-dimericneurotrophic properties.Neurotrophins act on specific receptors tyrosine kinases(TrK) A, for NGF, B, for BDNF, and NT-4/5 and C, for NT-3, andtheir expression is greater in the embryo 57.Nerve damage induces changes in the expression of growthfactors. This change affects the tissue without innervation,Schwann cells, dorsal horn of the spinal cord, and dorsal rootganglion. However, after nerve damage the synthesis of tho-se substances as well as of their receptors increases 58. Inthe experimental L5 SNL damage neurotrophic factor (GNF)

is increased in the L4-innervated territory with the retrogradetransport of neurotrophins to the dorsal root ganglion modi-fying the expression of brain derived neurotrophic factors(BDNF). Therefore, an influence of neurotrophic factors indamaged and intact neurons is seen. Neurotrophic factors(NGF) increase the expression of channels related withtransduction of the mechanical stimulus (TRPV4). Thus, coldhyperalgesia can be secondary to the abnormal expressionof TRPA1 and TRPM8 channels. Nerve growth factor besidescausing direct sensitization of peripheral nociceptors affectsimmune and sympathetic cells 59, while BDNF facilitates theexcitation of dorsal horn neurons 60. In experimental models,expression of those substances increases in the area re-lated with the damaged nerve secondary to constriction aswell as the corresponding dorsal root ganglion 61. Theendoneural injection of neurotrpphic factor causes buddingof synapses and signs of thermic hyperalgesia, while theperineural administration of this substance determines theforthcoming of mechanical hyperalgesia.Growth factors play a fundamental role in the developmentand maintenance of small neurons and the sympathetic ner-vous system. After nerve damage, -adrenergic receptors areincreased in the soma in intact axons, with the consequentsensitivity of those nerves to circulating adrenaline. In animal

models, the blockade of damaged fibers by local anestheticsreduces significantly their spontaneous activity and nervebudding in the sympathetic nervous system up to five weeksafter the lesion, with the blockade of NGF production by inhi-biting tyrosine kinase.

Nitric Oxide and Superoxide RadicalsSuperoxide radicals are released by mast cells and glia (as-trocytes and microglia). On the other hand, nitric oxide hasconstitutive endothelial and neuronal forms, while the indu-ced form is expressed in cells of the immunologic system.Nitric oxide causes hyperalgesia after injection in the skin andjoints 162 and it is implicated in central sensitization 48, in-creasing the effects of PG2 in neuropathic pain models

63.

Lysophosphatidic AcidLysophosphatidic acid (LPA) is derived from the lipid metabo-lism, it is released after tissue damage and might be involvedin neuropathic pain. Platelets are the greatest producers ofLPA and the plasma is its major source. Lysophosphatidicacid receptors (LPA1 to 4) are distributed in the central and peri-pheral nervous system. They are also coupled to proteinG12/13 and when activated, they activate GTPase and RHoAand a series of second messengers, including Rho kinaseor ROCK. The intrathecal injection of LPA in animals causesmechanical allodynia and thermal hyperalgesia. There is adrastic reduction of myelin-associated proteins (myelin basicand peripheral protein, MPB and PMP 22, respectively) andan increase in the expression of phosphokinase C andcalcium channels (Cav21) with nerve degeneration,synaptic budding, increased neuronal excitability 64.

NEUROPATHIC PAIN AND NERVE DEGENERATION

Calcium influx is one of the first events after nerve damage.Calcium initiates tissue cicatrization grouping vesicles in theaxolema around damaged distal and proximal nerve en-dings. The increase in intracellular calcium also activatescalcium-dependent protein kinases and other proteases(UPS) that facilitate the release of cytokines and destructionof microtubules and microfilaments, which are important inthe axonal transport of substances and in the mechanism ofneuropathic pain. This leads to an accumulation of SP, CGRP,nitric oxide, neurotrophic factors, and sodium channels that,together, amplify neuronal excitability 65.

Although peripheral lesions of C fibers lead to a reduction ofSP, neurotrophins (BDNF), receptors (VR1 and P2X3), andtype N high-voltage calcium channels in the dorsal horn ofthe spinal cord, there is ascending regulation of type III TTX-sensitive (TTXs) channels and translocation of TTX-resistant(TTXr) sodium channels from the soma to the neuroma, in-creasing nerve excitability 66. The expression of Nav 1.3 TTXschannels, whose kinetic characteristic is to be easily acti-vated and inactivated, can increase by two to 30-fold in mo-dels of dorsal root ganglion axotomy, ligature of the spinalnerve, chronic constrictive damage, diffuse nerve damage,diabetic neuropathy, and post-herpetic neuropathy 11.



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When the nerve fiber is intact (inflammation), excitatory neu-romediators increase in the dorsal horn of the spinal cord,as well as the expression of sodium channels (TTXr), whichfacilitates neuronal hyperexcitability and hinders the res-ponse to treatment with local anesthetics 66.In both situations described, especially in lesions of C fibers,

there can also be an increase in SP and BDNF in A fibers(low threshold mechanoreceptors), as well as budding ofthose fibers at the site of afferent connections of C fibers(lamina II), widening the receptive field of the neuron andleading to the interpretation of innocuous peripheral mecha-nical stimuli as aggressive 67. This explains, for example, themechanical allodynia that is seen in post-herpetic neural-gia 68. Sprouting of the sympathetic noradrenergic dorsal rootganglion axon around large-caliber neurons (A fibers) wouldbe another possibility, suggesting the hypothesis of activa-tion of sensitive afferent fibers after sympathetic stimula-tion 69. Besides, some disproportion between excitatory andpain suppression pathways can be present, with reduction

in the inhibitory activity of glycine, GABA, and opioids 66.

CENTRAL ASPECTS

In models of neuropathic pain in animals, the inhibitory effectof descending fibers originating in the periaqueductal graymatter and locus ceruleus can show a 50% reduction fromthe baseline. There is reduced efficacy of the opioid systemin the spinal cord, with reduction of -endorphins in the brainand spinal cord, with the consequent reduction of the anal-gesic effects of morphine, both by systemic and spinal admi-nistration. This suggests that opioid receptors or other factorsthat are necessary for the activation of the spinal opioid sys-

tem are compromised after nerve damaged 2,3. On the otherhand, programmed cell death can occur in dorsal horn neu-rons that express c-jun. This involves studies of the Bcl-2and Bax gene families that inhibit and favor cell death, res-pectively. In mice with sectioned nerve and in which the ex-pression of c-jun is increased, the Bcl-2/Bax relationship isreduced, indicating a tendency for apoptosis and deafferen-tation of post-synaptic spinal neurons 14.The destruction of the posterior cord or the gracilis nucleusipsilateral to the lesion can abolish mechanical allodynia inmice. On the other hand, allodynia can also be inhibited by theselective destruction of descending pathways of the brain-

stem and dorsolateral cord, indicating a role of ascendingand descending pathways in changes secondary to neu-ropathic pain. Thermal allodynia can be abolished by theinjection of lidocaine or cholecystokinin (CCK) receptor an-tagonists in the ventromedial area of the medulla (raphe mag-nus nucleus). Descending facilitation involving the medianraphe nucleus in the medulla (NRM) and CCK can occur innerve damage. Therefore, severing descendent fibers canreduce considerably mechanical or thermal allodynia in ani-mals. Medulla-spinal impulses are also capable to activatepost-synaptic sympathetic neurons that contribute for themaintenance of neuropathic pain 2,3,14.

As for the neurophysiological aspects of neuropathic pain inSNL, the spontaneous neuronal activity of somatosensorialregions of the thalamus (ventral posteromedial nucleus, VPM,and ventral posterior lateral nucleus, VPL) is increased andit can be inhibited by substances that block the expressionof Nav 1.3 sodium channels. On the other hand, functional

imaging of the thalamus contralateral to the neuropathic painshows reduced metabolism. In the cerebral cortex, the beha-vior of 10% of the neurons is similar to the thalamic neurons,especially those located in the periphery of the deafferentedzone of the primary somesthetic cortex. The electroence-phalogram shows an increase in theta frequency (4 to 5 Hz)and the metabolism or the cortical output of the insular, pos-terior parietal, pre-frontal, and cingulate areas is elevated.The opposite is seen in the medial (Brodmann area 24), andanterior and perigenual (Brodmann areas 32 and 35) cin-gulate cortices. Some researchers demonstrated that theincreased perigenual output after motor cortical stimulation

of the Gasser ganglion reduces pain severity. This streng-thens the hypothesis of the relationship between perigenualchanges and failure of the descending inhibitory control. Areduction of opioid receptors in the periaqueductal gray mat-ter, in medial thalamus, pre-frontal cortex, and nsula due tointernalization is also seen. This reduction is bilateral andsymmetrical and preponderant in the ipsilateral side in thecase of a central lesion 2.

CONCLUSION

Neuropathic pain is still a challenge for clinical and experi-mental researchers. Its mechanisms, which are complex andnot completely understood result occasionally in dynamicswith contradictory results. Understanding the neurobiology ofneuropathic pain is a step towards the improvement in thetreatment of this syndrome. This understanding may resultin the development of drugs aimed at specific targets witheffective responses.

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RESUMENKraychete DC, Gozzani JL, Kraychete AC Dolor Neuroptico

Aspectos Neuroqumicos.

JUSTIFICATIVA Y OBJETIVOS:El dolor Neuroptico lo causa lalesin o inflamacin del sistema nervioso. Es un sndrome com-plejo, con mecanismos biolgicos poco aclarados, que envuelveteoras inflamatorias e inmunes. El objetivo de esta revisin fuedescribir los principales factores biolgicos relacionados con eldolor Neuroptico, asociando de forma lgica a las hiptesis su-geridas por la literatura.

CONTENIDO:Fueron descritos los principales neuromediadores,canales inicos y clulas, incluyendo las del sistema inmune invo-lucrados en la excitabilidad neuronal, como tambin la posiblesecuencia de activacin o interaccin de esos agentes en la alte-

racin neuroplstica proveniente e la agresin al nervio.

CONCLUSIONES:De ese estudio, se pudo concluir que los avan-ces en el conocimiento de la fisiopatologa del dolor Neuroptico,pueden determinar nuevos objetivos para el abordaje farmacolgicode ese sndrome.


dor neuropatoca-08

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