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Behavior of Ion Channels Controlled by Electric Potential Difference and of Toll-Type Receptors in Neuropathic Pain Pathophysiol

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Behavior of Ion Channels Controlled by Electric Potential Difference and of Toll-Type Receptors in Neuropathic Pain Pathophysiol Rev Dor. São Paulo, 2016;17(Suppl 1):S43-5 REVIEW ARTICLE Behavior of ion channels controlled by electric potential difference and of Toll-type receptors in neuropathic pain pathophysiology O comportamento dos canais iônicos controlados por diferença de potencial elétrico e dos receptores do tipo Toll na fisiopatologia da dor neuropática André Prato Schmidt1, Sérgio Renato Guimarães Schmidt2 DOI 10.5935/1806-0013.20160046 ABSTRACT mento de quadros dolorosos crônicos evidenciam a capacidade de modulá-los farmacologicamente em novas estratégias terapêuticas. BACKGROUND AND OBJECTIVES: Neuropathic pain is a severe and refrac- CONCLUSÃO: Evidências recentes sugerem que bloqueadores seletivos de ca- tory medical condition, for which only partially effective treatments are currently nais de sódio e fármacos ativadores ou moduladores dos canais de potássio repre- available. Recent experimental data on the role of voltage-gated ion channels, sentam um alvo relevante e promissor na busca por novas opções no tratamento particularly sodium and potassium channels, have been described. In this brief da dor neuropática. review, we aimed at addressing the role of sodium and potassium channels in the Descritores: Canais iônicos, Canais de potássio, Canais de sódio, Dor crônica, pathophysiology of neuropathic pain and recent evidences about their role as a Dor neuropática. new therapeutic target in painful conditions. CONTENTS: Pharmacological and biophysical studies have shown that voltage- INTRODUCTION gated sodium channels, particularly Nav1.3, Nav1.7, Nav1.8, and Nav1.9 isoforms are important in the pathophysiology of neuropathic pain. Similarly, the involve- Neuropathic pain (NP) is a multifactorial event involving different central ment of voltage-gated potassium channels, especially KV1 and KV7 isoforms, has and peripheral nervous system (CNS, PNS) components. However, in spite been clearly shown in the establishment of chronic painful conditions. Recent of its perception usually being complex, NP is often related to peripheral evidences that ion sodium and potassium channels dysfunction is involved in the origin dependent on the electric activity present in sensory neurons respon- development of chronic painful conditions corroborate the possibility of phar- sible for tissue and viscerae innervation1. macologically modulate them as new therapeutic strategies. Among such structures, the role of electric potential-gated or voltage-gated CONCLUSION: Recent evidences suggest that selective sodium channel block- ion channels is to be highlighted. In PNS, these sensory neurons are essen- ers and potassium channels activating of modulating drugs are important and tially located in dorsal roots ganglia where distal axons in peripheral nerves promising targets in the search for new options to treat neuropathic pain. responsible for the innervation of distant targets such as skin emerge. In Keywords: Chronic pain, Ion channels, Neuropathic pain, Potassium channels, peripheral nerve trauma, these neuronal structures have the ability to de- Sodium channels. velop adaptative neuroplastic phenomena, promoting axonal remyelination and regeneration. RESUMO However, this physiologic response to trauma might be associated to patho- logic phenomena, inducing nociceptive sensory neurons sensitization and, JUSTIFICATIVA E OBJETIVOS: A dor neuropática constitui-se em uma subsequently, chronic stimulation of peripheral painful transmission path- condição clínica grave e refratária, para a qual apenas tratamentos com eficácia ways generating a painful chronicity process1-3. parcial estão disponíveis. Estudos experimentais recentes sobre o papel relevante Physiologic nociceptive response is essentially maintained by a frequency de canais iônicos controlados por diferença de potencial elétrico ou voltagem, of action potentials mediated by ion channels present in afferent fibers. So, especialmente canais de sódio e potássio, tem sido descritos. Nesta breve revisão, one may infer that in chronic pain there is increase and maintenance of objetivou-se abordar o papel dos canais de sódio e potássio na fisiopatologia da transmission of action potential coming from the periphery and responsible dor neuropática e as recentes evidências a respeito do seu papel como novo alvo for central interpretation of noxious stimuli. terapêutico em quadros dolorosos. In this process, several components are involved, including increased neural CONTEÚDO: Estudos farmacológicos e biofísicos tem demonstrado que os excitability, decreased threshold for action potential onset, action poten- canais de sódio dependentes de voltagem, particularmente as isoformas Na 1.3, v tials amplification, spontaneous discharges, among other alterations, all Na 1.7, Na 1.8 e Na 1.9 são relevantes na fisiopatologia da dor neuropática. De v v v involving electric potential difference-gated ion channels3-6. forma similar, o envolvimento dos canais de potássio dependentes de voltagem, This study aimed at briefly addressing aspects involved in pathophysiology especialmente as isoformas K 1 e K 7, tem sido claramente demonstrado no es- v v and pharmacology of major electric potential difference-gated or voltage- tabelecimento de quadros dolorosos crônicos. As evidências recentes de que a gated ion channels present in axonal membrane of dorsal root ganglion disfunção de canais iônicos de sódio e potássio está envolvida no desenvolvi- neurons represented by voltage-gated sodium channels (Nav) and voltage- gated potassium channels (K+). ELECTRIC POTENTIAL DIFFERENCE-GATED SODIUM CHAN- 1. Hospital de Clínicas de Porto Alegre, Anestesiologista e Certificado na Área de Atuação em Dor, Serviço NELS (Na ) de Anestesia e Medicina Perioperatória, Corresponsável pelo Centro de Ensino e Treinamento da Santa Casa V de Porto Alegre, Universidade Federal de Ciências da Saúde de Porto Alegre, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS); Centro Interdisciplinar de Estudos e Tratamento da Electric activity of peripheral sensory neurons is closely related to their Dor, Centro Clínico Mãe de Deus, Porto Alegre, RS, Brasil. ability to generate and transport action potential promoted by voltage- 2. Anestesiologista e Certificado na Área de Atuação em Dor, SOS Dor – Centro Interdisciplinar de Estudos e Tratamento da Dor, Centro Clínico Mãe de Deus, Porto Alegre, RS, Brasil. gated ion channels (or ionophores) (Nav) located along axonal membrane. This essential Nav role in neural electrogenesis has brought to light a new Conflict of interests: none – Sponsoring sources: none. important target for new therapeutic approaches aiming at attenuating 7-11 Correspondence to: neural firing resulting in painful response . André P. Schmidt Na remain inactive and closed at rest, but develop conformational and Centro Interdisciplinar de Tratamento da Dor – SOS Dor v Centro Clínico do Hospital Mãe de Deus structural changes in response to initial membrane depolarization, caus- Rua Costa 30, sala 210 ing a cyclic phenomenon of channels opening and closing during physi- 90110-270 Porto Alegre, RS, Brasil. ologic sensory transmission process. Transient Na opening allows the flow E-mail: [email protected] v of sodium ions toward the concentration gradient, promoting a neuronal © Sociedade Brasileira para o Estudo da Dor depolarization transmembrane current leading closest axonal membrane to 43 Rev Dor. São Paulo, 2016;17(Suppl 1):S43-5 Schmidt AP and Schmidt SR the threshold to generate action potential. Nav1.8 isoforms and of axonal biochemical mediators (p38 and protein Most Nav are rapidly inactivated opening, then suffering conformational kinase activated by mitogen ERK1/2) changes for a new activation cycle. Nav are heteromultimer made up of a Previous studies have shown significant genetic relation of hereditary pain- α 23,24 larger subunit called alpha ( ) and of smaller auxiliary subunits called beta ful syndromes related to Nav disorders in humans and animal models . β α ( ). Subunit is needed to form essential functional structure of Nav and SCN9A gene mutations, responsible for Nav1.7 channel transcription, were subunits β modulate channel biophysical properties, in addition to regulat- identified in two severe painful syndromes (hereditary erythromelalgia and 23,24 ing channels transport and fixation next to the axonal membrane. paroxysmal extreme painful disorder) . Mutations with loss of Nav1.7 Each domain has 6 potential segments in α-helix (S1 to S6) actively par- gene function were also identified in patients with congenital insensitivity 25 ticipating in Nav activation and closing process. Nine mammal genes have to pain . been described so far (SCN1A to SCN5A; SCN8A to SCN11A) which are As presented, there is significant and abundant information in the literature related at molecular level to different α subunits, causing the formation of about the role of voltage-gated Na+ ionophores in painful transmission, in nine different sodium channels isoforms (N av1.1 to Nav1.9), all sharing addition to the specific role of each subunit in the generation and mainte- similar central structure, but with different amino acids sequences and, as a nance of chronic pain. To date, unspecific Nav blockers, such as lidocaine consequence, different kinetics and voltage-gated properties. and carbamazepine have been significantly effective in different clinical Structurally, isoforms Nav1.1, Nav1.2, Nav1.3 and Nav1.7 are similar to protocols to treat chronic pain, especially NP. However, their partial ef- each other.
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