{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T06:14:04Z","timestamp":1769580844635,"version":"3.49.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,12,14]],"date-time":"2023-12-14T00:00:00Z","timestamp":1702512000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["368482240\/GRK2416"],"award-info":[{"award-number":["368482240\/GRK2416"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["LA 2740\/3\u20131"],"award-info":[{"award-number":["LA 2740\/3\u20131"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["363055819\/GRK2415"],"award-info":[{"award-number":["363055819\/GRK2415"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Comput. Neurosci."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Patients with small fiber neuropathy (SFN) suffer from neuropathic pain, which is still a therapeutic problem. Changed activation patterns of mechano-insensitive peripheral nerve fibers (CMi) could cause neuropathic pain. However, there is sparse knowledge about mechanisms leading to CMi dysfunction since it is difficult to dissect specific molecular mechanisms in humans. We used an <jats:italic>in-silico<\/jats:italic> model to elucidate molecular causes of CMi dysfunction as observed in single nerve fiber recordings (microneurography) of SFN patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Approach<\/jats:title><jats:p>We analyzed microneurography data from 97 CMi-fibers from healthy individuals and 34 of SFN patients to identify activity-dependent changes in conduction velocity. Using the NEURON environment, we adapted a biophysical realistic preexisting CMi-fiber model with ion channels described by Hodgkin-Huxley dynamics for identifying molecular mechanisms leading to those changes. Via a grid search optimization, we assessed the interplay between different ion channels, Na-K-pump, and resting membrane potential.<\/jats:p><\/jats:sec><jats:sec><jats:title>Main results<\/jats:title><jats:p>Changing a single ion channel conductance, Na-K-pump or membrane potential individually is not sufficient to reproduce in-silico CMi-fiber dysfunction of unchanged activity-dependent conduction velocity slowing and quicker normalization of conduction velocity after stimulation as observed in microneurography. We identified the best combination of mechanisms: increased conductance of potassium delayed-rectifier and decreased conductance of Na-K-pump and depolarized membrane potential. When the membrane potential is unchanged, opposite changes in Na-K-pump and ion channels generate the same effect.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Our study suggests that not one single mechanism accounts for pain-relevant changes in CMi-fibers, but a combination of mechanisms. A depolarized membrane potential, as previously observed in patients with neuropathic pain, leads to changes in the contribution of ion channels and the Na-K-pump. Thus, when searching for targets for the treatment of neuropathic pain, combinations of several molecules in interplay with the membrane potential should be regarded.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fncom.2023.1265958","type":"journal-article","created":{"date-parts":[[2023,12,14]],"date-time":"2023-12-14T13:01:21Z","timestamp":1702558881000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["A modelling study to dissect the potential role of voltage-gated ion channels in activity-dependent conduction velocity changes as identified in small fiber neuropathy patients"],"prefix":"10.3389","volume":"17","author":[{"given":"Anna","family":"Maxion","sequence":"first","affiliation":[]},{"given":"Ekaterina","family":"Kutafina","sequence":"additional","affiliation":[]},{"given":"Maike F.","family":"Dohrn","sequence":"additional","affiliation":[]},{"given":"Pierre","family":"Sacr\u00e9","sequence":"additional","affiliation":[]},{"given":"Angelika","family":"Lampert","sequence":"additional","affiliation":[]},{"given":"Jenny","family":"Tigerholm","sequence":"additional","affiliation":[]},{"given":"Barbara","family":"Namer","sequence":"additional","affiliation":[]}],"member":"1965","published-online":{"date-parts":[[2023,12,14]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1079","DOI":"10.1152\/physrev.00052.2017","article-title":"The role of voltage-gated sodium channels in pain signaling","volume":"99","author":"Bennett","year":"2019","journal-title":"Physiol. Rev."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.1002\/ejp.1226","article-title":"Hyperpolarization-activated channels shape temporal patterns of ectopic spontaneous discharge in C-nociceptors after peripheral nerve injury","volume":"22","author":"Bernal","year":"2018","journal-title":"Eur. J. Pain"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1111\/jns5.12071","article-title":"Painful neuropathies: the emerging role of sodium channelopathies","volume":"19","author":"Brouwer","year":"2014","journal-title":"J. Peripher. Nerv. Syst."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1575","DOI":"10.1016\/S1388-2457(01)00595-8","article-title":"Excitability of human axons","volume":"112","author":"Burke","year":"2001","journal-title":"Clin. Neurophysiol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"S7","DOI":"10.1097\/j.pain.0000000000000368","article-title":"Potassium channels in neuropathic pain: advances, challenges, and emerging ideas","volume":"157","author":"Busserolles","year":"2016","journal-title":"Pain"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1002\/mus.25082","article-title":"Small fiber neuropathy: getting bigger!","volume":"53","author":"Chan","year":"2016","journal-title":"Muscle Nerve"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1523\/JNEUROSCI.23-04-01169.2003","article-title":"Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain","volume":"23","author":"Chaplan","year":"2003","journal-title":"J. Neurosci."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/nrdp.2017.2","article-title":"Neuropathic pain","volume":"3","author":"Colloca","year":"2017","journal-title":"Nat. Rev. Dis. Primer"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1038\/nature05413","article-title":"An SCN9A channelopathy causes congenital inability to experience pain","volume":"444","author":"Cox","year":"2006","journal-title":"Nature"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1113\/jphysiol.2007.145383","article-title":"Conduction velocity is regulated by sodium channel inactivation in unmyelinated axons innervating the rat cranial meninges","volume":"586","author":"De Col","year":"2008","journal-title":"J. Physiol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1113\/jphysiol.2011.220624","article-title":"Repetitive activity slows axonal conduction velocity and concomitantly increases mechanical activation threshold in single axons of the rat cranial dura","volume":"590","author":"De Col","year":"2012","journal-title":"J. Physiol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"3335","DOI":"10.1523\/JNEUROSCI.5156-03.2004","article-title":"Differential distribution and function of hyperpolarization-activated channels in sensory neurons and mechanosensitive fibers","volume":"24","author":"Doan","year":"2004","journal-title":"J. Neurosci."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1016\/j.neuron.2006.10.006","article-title":"SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes","volume":"52","author":"Fertleman","year":"2006","journal-title":"Neuron"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1111\/j.1399-0004.2007.00790.x","article-title":"Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations","volume":"71","author":"Goldberg","year":"2007","journal-title":"Clin. Genet."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1038\/s41583-021-00444-w","article-title":"The physiological function of different voltage-gated sodium channels in pain","volume":"22","author":"Goodwin","year":"2021","journal-title":"Nat. Rev. Neurosci."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1007\/978-3-662-46450-2_3","article-title":"Sodium channels and pain","volume":"227","author":"Habib","year":"2015","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.1162\/neco.1997.9.6.1179","article-title":"The NEURON simulation environment","volume":"9","author":"Hines","year":"1997","journal-title":"Neural Comput."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/neuro.11.001.2009","article-title":"NEURON and Python","volume":"3","author":"Hines","year":"2009","journal-title":"Front. 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Res."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1038\/nn1839","article-title":"Presynaptic Ca2+ buffers control the strength of a fast post-tetanic hyperpolarization mediated by the alpha3 Na(+)\/K(+)-ATPase","volume":"10","author":"Kim","year":"2007","journal-title":"Nat. Neurosci."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"e0161789","DOI":"10.1371\/journal.pone.0161789","article-title":"SCN10A mutation in a patient with erythromelalgia enhances C-Fiber activity dependent slowing","volume":"11","author":"Kist","year":"2016","journal-title":"PLoS One"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"2040","DOI":"10.1016\/j.pain.2012.05.017","article-title":"High spontaneous activity of C-nociceptors in painful polyneuropathy","volume":"153","author":"Kleggetveit","year":"2012","journal-title":"Pain"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/B978-0-12-809324-5.24208-9","article-title":"5.09 - Sodium Channels\u2606","volume-title":"The Senses: A Comprehensive Reference (Second Edition)","author":"K\u00f6rner","year":"2020"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1178","DOI":"10.1093\/brain\/awh476","article-title":"Altered nerve excitability properties in established diabetic neuropathy","volume":"128","author":"Krishnan","year":"2005","journal-title":"Brain"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1093\/brain\/awn052","article-title":"Activity-dependent excitability changes suggest Na+\/K+ pump dysfunction in diabetic neuropathy","volume":"131","author":"Krishnan","year":"2008","journal-title":"Brain"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1152\/jn.00360.2019@apsselect.2020.7.issue-2","article-title":"The small fiber neuropathy NaV1.7 I228M mutation: impaired neurite integrity via bioenergetic and mitotoxic mechanisms, and protection by dexpramipexole","volume":"123","author":"Lee","year":"2020","journal-title":"APSselect"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.1016\/j.neuroscience.2006.10.048","article-title":"Role of peripheral hyperpolarization-activated cyclic nucleotide-modulated channel pacemaker channels in acute and chronic pain models in the rat","volume":"144","author":"Luo","year":"2007","journal-title":"Neuroscience"},{"key":"ref30","author":"Maxion","year":"2023"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1113\/jphysiol.2008.162941","article-title":"Microneurographic assessment of C-fibre function in aged healthy subjects","volume":"587","author":"Namer","year":"2009","journal-title":"J. Physiol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"1637","DOI":"10.1097\/j.pain.0000000000000229","article-title":"Specific changes in conduction velocity recovery cycles of single nociceptors in a patient with erythromelalgia with the I848T gain-of-function mutation of Nav1.7","volume":"156","author":"Namer","year":"2015","journal-title":"Pain"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1002\/mus.20367","article-title":"Hyperexcitable polymodal and insensitive nociceptors in painful human neuropathy","volume":"32","author":"Ochoa","year":"2005","journal-title":"Muscle Nerve"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1016\/S1474-4422(13)70158-3","article-title":"Peripheral neuropathy in mitochondrial disorders","volume":"12","author":"Pareyson","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1152\/jn.00315.2020","article-title":"Excitation properties of computational models of unmyelinated peripheral axons","volume":"125","author":"Pelot","year":"2021","journal-title":"J. Neurophysiol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"e103556","DOI":"10.1371\/journal.pone.0103556","article-title":"Differential axonal conduction patterns of mechano-sensitive and mechano-insensitive nociceptors \u2013 a combined experimental and modelling study","volume":"9","author":"Petersson","year":"2014","journal-title":"PLoS One"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1072629","DOI":"10.3389\/fcell.2023.1072629","article-title":"Neuropathic pain: mechanisms and therapeutic strategies","volume":"11","author":"Petroianu","year":"2023","journal-title":"Front. Cell Dev. Biol."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"3102","DOI":"10.1016\/j.celrep.2017.11.066","article-title":"Functional and molecular characterization of mechanoinsensitive \u201csilent\u201d nociceptors","volume":"21","author":"Prato","year":"2017","journal-title":"Cell Rep."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1016\/j.pain.2004.04.034","article-title":"Symptoms and signs in patients with suspected neuropathic pain","volume":"110","author":"Rasmussen","year":"2004","journal-title":"Pain"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"2248","DOI":"10.1038\/s41467-020-15791-y","article-title":"An axon-specific expression of HCN channels catalyzes fast action potential signaling in GABAergic interneurons","volume":"11","author":"Roth","year":"2020","journal-title":"Nat. Commun."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1007\/BF00242018","article-title":"Delayed responses to electrical stimuli reflect C-fiber responsiveness in human microneurography","volume":"104","author":"Schmelz","year":"1995","journal-title":"Exp. Brain Res."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1523\/JNEUROSCI.15-01-00333.1995","article-title":"Novel classes of responsive and unresponsive C nociceptors in human skin","volume":"15","author":"Schmidt","year":"1995","journal-title":"J. Neurosci."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1016\/j.jbspin.2017.11.002","article-title":"Small fiber neuropathy: diagnosis, causes, and treatment","volume":"85","author":"S\u00e8ne","year":"2018","journal-title":"Joint Bone Spine"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1016\/j.pain.2010.10.039","article-title":"Double and triple spikes in C-nociceptors in neuropathic pain states: an additional peripheral mechanism of hyperalgesia","volume":"152","author":"Serra","year":"2011","journal-title":"Pain"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1007\/s11916-022-01044-8","article-title":"Small fiber neuropathy","volume":"26","author":"Strand","year":"2022","journal-title":"Curr. Pain Headache Rep."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1016\/j.bpj.2014.12.034","article-title":"C-Fiber recovery cycle Supernormality depends on ion concentration and Ion Channel permeability","volume":"108","author":"Tigerholm","year":"2015","journal-title":"Biophys. J."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"1721","DOI":"10.1152\/jn.00777.2012","article-title":"Modeling activity-dependent changes of axonal spike conduction in primary afferent C-nociceptors","volume":"111","author":"Tigerholm","year":"2014","journal-title":"J. Neurophysiol."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/0006-8993(74)90489-2","article-title":"Identification of afferent C units in intact human skin nerves","volume":"67","author":"Torebj\u00f6rk","year":"1974","journal-title":"Brain Res."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"eaam6072","DOI":"10.1126\/scitranslmed.aam6072","article-title":"Hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) ion channels drive pain in mouse models of diabetic neuropathy","volume":"9","author":"Tsantoulas","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1016\/j.tins.2013.12.002","article-title":"Opening paths to novel analgesics: the role of potassium channels in chronic pain","volume":"37","author":"Tsantoulas","year":"2014","journal-title":"Trends Neurosci."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"10184","DOI":"10.1523\/JNEUROSCI.19-22-10184.1999","article-title":"Functional attributes discriminating mechano-insensitive and mechano-responsive C nociceptors in human skin","volume":"19","author":"Weidner","year":"1999","journal-title":"J. Neurosci."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"1708","DOI":"10.1016\/j.pain.2014.05.021","article-title":"Inflammatory and neuropathic pain are rapidly suppressed by peripheral block of hyperpolarisation-activated cyclic nucleotide-gated ion channels","volume":"155","author":"Young","year":"2014","journal-title":"Pain"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"e25382","DOI":"10.7554\/eLife.25382","article-title":"Ionic mechanisms underlying history-dependence of conduction delay in an unmyelinated axon","volume":"6","author":"Zhang","year":"2017","journal-title":"elife"}],"container-title":["Frontiers in Computational Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncom.2023.1265958\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,14]],"date-time":"2023-12-14T13:01:29Z","timestamp":1702558889000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncom.2023.1265958\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,14]]},"references-count":53,"alternative-id":["10.3389\/fncom.2023.1265958"],"URL":"https:\/\/doi.org\/10.3389\/fncom.2023.1265958","relation":{},"ISSN":["1662-5188"],"issn-type":[{"value":"1662-5188","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,14]]},"article-number":"1265958"}}