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Schmerz und Schmerzlosigkeit

Mutationen spannungsabhängiger Natriumkanäle

Pain and analgesia

Mutations of voltage-gated sodium channels

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Zusammenfassung

Spannungsabhängige Natriumkanäle (Nav) sind für die Generierung und Weiterleitung von Aktionspotentialen in erregbaren Zellen, und somit auch für die Funktion sensibler Nerven, verantwortlich. In den letzten 20 Jahren konnten drei Nav-Untereinheiten in sensorischen Afferenzen identifiziert werden, Nav1.7, Nav1.8 und Nav1.9, denen eine spezifische Rolle für die Funktion nozizeptiver Neurone zugesprochen wird. Bislang konnten keine selektiven Natriumkanalblocker in der Klinik etabliert werden. Durch die Translation präklinischer Daten in klinisch manifeste Krankheitsbilder erhöht sich jedoch die Relevanz der obigen Nav-Untereinheiten für die Schmerzentstehung beim Menschen. Im Mittelpunkt steht seit zehn Jahren Nav1.7, für den eine sehr große Anzahl von hereditären Mutationen nachgewiesen wurde. Sogenannte Gain-of-function-Mutationen (Verstärkung der Genaktivität) von Nav1.7 sind kausal für die Schmerzsymptome der primären Erythromelalgie (anfallsartige Hauterkrankung mit Rötung und Überwärmung der distalen Extremitäten) und die paroxysmale extreme Schmerzstörung. Zudem wurde ein Zusammenhang einiger Nav1.7-Mutationen mit schmerzhaften idiopathischen Small-fiber-Neuropathien (schmerzhafte sensorische Neuropathien) nachgewiesen. Umgekehrt führen „Loss-of-function“-Nav1.7-Mutationen (Drosselung der Genaktivität) zu einer kongenitalen Schmerzlosigkeit. Erst kürzlich konnten mehrere „Gain-of-function“-Mutationen in Nav1.8 und Nav1.9 bei Patienten mit schmerzhaften Neuropathien nachgewiesen werden, wobei auch eine der „Gain-of-function“-Nav1.9-Mutationen zur kompletten Schmerzlosigkeit führte. Dieser Artikel bietet eine Übersicht über die bislang publizierten Studien zu schmerzhaften Nav-Mutationen mit klinischer Relevanz, und stellt die damit möglichen Konsequenzen für die Therapie verschiedener Schmerzsymptome in Aussicht.

Abstract

Voltage-gated sodium channels (Navs) are crucial for the generation and propagation of action potentials in all excitable cells, and therefore for the function of sensory neurons as well. Preclinical research over the past 20 years identified three Nav-isoforms in sensory neurons, namely Nav1.7, Nav1.8 and Nav1.9. A specific role for the function of nociceptive neurons was postulated for each. Whereas no selective sodium channel inhibitors have been established in the clinic so far, the relevance of all three isoforms regarding the pain sensitivity in humans is currently undergoing a remarkable verification through the translation of preclinical data into clinically manifest pictures. For the last ten years, Nav1.7 has been the main focus of clinical interest, as a large number of hereditary mutants were identified. The so-called “gain-of-function” mutations of Nav1.7 cause the pain syndromes hereditary erythromelalgia and paroxysmal extreme pain disorder. In addition, several Nav1.7 mutants were shown to be associated with small-fiber neuropathies. On the contrary, “loss-of-function” Nav1.7 mutants lead to a congenital insensitivity to pain. Recently, several gain-of-function mutations in Nav1.8 and Nav1.9 have been identified in patients suffering from painful peripheral neuropathies. However, another gain-of-function Nav1.9 mutation is associated with congenital insensitivity to pain. This review offers an overview of published work on painful Nav mutations with clinical relevance, and proposes possible consequences for the therapy of different pain symptoms resulting from these findings.

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Authors and Affiliations

  1. Klinik für Anästhesiologie und Intensivmedizin, Medizinische Hochschule Hannover, Carl-Neuberg-Straße 1, 30625, Hannover, Deutschland

    M. J. Eberhardt &  A. Leffler

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Correspondence to A. Leffler.

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M. J. Eberhardt und A. Leffler geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

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Eberhardt, M.J., Leffler, A. Schmerz und Schmerzlosigkeit . Schmerz 31, 14–22 (2017). https://doi.org/10.1007/s00482-016-0139-0

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