Differential Axonal Conduction Patterns of Mechano- Sensitive and Mechano-Insensitive Nociceptors – A Combined Experimental and Modelling Study

dc.contributor.authorPetersson, Marcus E.
dc.contributor.authorObreja, Otilia
dc.contributor.authorLampert, Angelika
dc.contributor.authorCarr, Richard W.
dc.contributor.authorSchmelz, Martin
dc.contributor.authorFransén, Erik
dc.date.accessioned2014-09-15
dc.date.available2023-10-09T15:35:21Z
dc.date.created2014
dc.date.issued2014-09-15
dc.description.abstractCutaneous pain sensations are mediated largely by -nociceptors consisting of both mechano-sensitive (CM) and mechanoinsensitive(CMi) fibres that can be distinguished from one another according to their characteristic axonal properties. In healthy skin and relative to CMi fibres, CM fibres show a higher initial conduction velocity, less activity-dependent conduction velocity slowing, and less prominent post-spike supernormality. However, after ensitization with nerve growth factor, the electrical signature of CMi fibres changes towards a profile similar to that of CM fibres. Here we take a combined experimental and modelling approach to examine the molecular basis of such alterations to the excitation thresholds. Changes in electrical activation thresholds and activity-dependent slowing were examined in vivo using single-fibre recordings of CM and CMi fibres in domestic pigs following NGF application. Using computational modelling, we investigated which axonal mechanisms contribute most to the electrophysiological differences between the fibre classes. Simulations of axonal conduction suggest that the differences between CMi and CM fibres are strongly influenced by the densities of the delayed rectifier potassium channel (Kdr), the voltage-gated sodium channels NaV1.7 and NaV1.8, and the Na+/K+-ATPase. Specifically, the CM fibre profile required less Kdr and NaV1.8 in combination with more NaV1.7 and Na+/K+- ATPase. The difference between CM and CMi fibres is thus likely to reflect a relative rather than an absolute difference in protein expression. In support of this, it was possible to replicate the experimental reduction of the ADS pattern of CMi nociceptors towards a CM-like pattern following intradermal injection of nerve growth factor by decreasing the contribution of Kdr (by 50%), increasing the Na+/K+-ATPase (by 10%), and reducing the branch length from 2 cm to 1 cm. The findings highlight key molecules that potentially contribute to the NGF-induced switch in nociceptors phenotype, in particular NaV1.7 which has already been identified clinically as a principal contributor to chronic pain states such as inherited erythromelalgia.en
dc.identifier.citationPLoS ONE 9.8 (2014) <http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0103556>
dc.identifier.opus-id5097
dc.identifier.urihttps://open.fau.de/handle/openfau/5097
dc.identifier.urnurn:nbn:de:bvb:29-opus4-50973
dc.language.isoen
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/de/deed.de
dc.subjectAction potentials
dc.subjectAxons
dc.subjectElectrical stimulation
dc.subjectIntradermal injections
dc.subjectIon channels
dc.subjectMembrane potential
dc.subjectNerve fibers
dc.subjectNociceptors
dc.subject.ddcDDC Classification::6 Technik, Medizin, angewandte Wissenschaften :: 61 Medizin und Gesundheit :: 610 Medizin und Gesundheit
dc.titleDifferential Axonal Conduction Patterns of Mechano- Sensitive and Mechano-Insensitive Nociceptors – A Combined Experimental and Modelling Studyen
dc.typearticle
dcterms.publisherFriedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
local.journal.issue8
local.journal.titlePLoS ONE
local.journal.volume9
local.sendToDnbfree*
local.subject.fakultaetMedizinische Fakultät
local.subject.gnd-
local.subject.sammlungUniversität Erlangen-Nürnberg / Open Access Artikel ohne Förderung / Open Access Artikel ohne Förderung 2014
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