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Optimized electrical stimulation of C-nociceptors in humans based on the chronaxie of porcine C-fibers

  • Author Footnotes
    † Present address: Department of Anesthesiology University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland; phone: +41 61 32 86543; fax: +41 61 265 57 20;
    ,
    Author Footnotes
    ‡ Authors contributed equally to the manuscript
    Tobias Schneider
    Correspondence
    Address of correspondence: Tobias Schneider, Mannheim Center Translational Neuroscience (MCTN), Dept. Experimental Pain Research, Ludolf-Krehl-Str. 13-17, 68167 Mannheim, phone: +49 621 383-71650, fax: +49 621 383-71651
    Footnotes
    † Present address: Department of Anesthesiology University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland; phone: +41 61 32 86543; fax: +41 61 265 57 20;
    ‡ Authors contributed equally to the manuscript
    Affiliations
    Department of Experimental Pain Research, Mannheim Center Translational Neuroscience (MCTN), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.

    Chronic pain unit, Department of Anesthesiology, University Hospital Basel, Basel, Switzerland
    Search for articles by this author
  • Author Footnotes
    † Present address: Department of Anesthesiology University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland; phone: +41 61 32 86543; fax: +41 61 265 57 20;
    ,
    Author Footnotes
    ‡ Authors contributed equally to the manuscript
    Julia Filip
    Footnotes
    † Present address: Department of Anesthesiology University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland; phone: +41 61 32 86543; fax: +41 61 265 57 20;
    ‡ Authors contributed equally to the manuscript
    Affiliations
    Department of Experimental Pain Research, Mannheim Center Translational Neuroscience (MCTN), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
    Search for articles by this author
  • Sabrina Soares
    Affiliations
    Department of Experimental Pain Research, Mannheim Center Translational Neuroscience (MCTN), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
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  • Kyra Sohns
    Affiliations
    Department of Experimental Pain Research, Mannheim Center Translational Neuroscience (MCTN), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
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  • Richard Carr
    Affiliations
    Department of Experimental Pain Research, Mannheim Center Translational Neuroscience (MCTN), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
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  • Roman Rukwied
    Affiliations
    Department of Experimental Pain Research, Mannheim Center Translational Neuroscience (MCTN), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
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  • Martin Schmelz
    Affiliations
    Department of Experimental Pain Research, Mannheim Center Translational Neuroscience (MCTN), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
    Search for articles by this author
  • Author Footnotes
    † Present address: Department of Anesthesiology University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland; phone: +41 61 32 86543; fax: +41 61 265 57 20;
    ‡ Authors contributed equally to the manuscript
Published:January 17, 2023DOI:https://doi.org/10.1016/j.jpain.2023.01.009

      Highlights:

      • Human skin C-nociceptors have an unexpectedly long chronaxie (about 15 ms)
      • Half-sine stimuli adapted to long chronaxie facilitate electrical stimulation of skin nociceptors
      • Currents for excitation of polymodal C-nociceptors in pig paralleled pain ratings in humans

      Abstract

      Classically, to electrically excite C-nociceptors, rectangular pulses are used with a duration close to the estimated chronaxie of C-fibres (about 2 ms). Recent results using slow depolarizing stimuli suggest longer chronaxies. We therefore set out to optimize C-fiber stimulation based on recordings of single C-nociceptors in-vivo and C-fiber compound-action-potentials (C-CAP) ex-vivo using half-sine shaped stimuli of durations between 1 and 250ms. Single fiber (n=45) recording in pigs revealed high chronaxie values for C-touch fibers (15.8 ms), polymodal- (14.2 ms) and silent-nociceptors (16.8 ms). Activation thresholds decreased 2-3fold in all fiber classes when increasing the duration of half-sine pulses from 1 to 25 ms (p<0.05). C-CAPs strength-duration curves of the pig saphenous nerve (n=7) showed the highest sensitivity for half-sine durations between 10 and 25 ms. Half-maximum currents for C-CAPS were reduced 3fold compared to rectangular pulses (p<0.01) whereas the opposite was found for A-fiber compound action potentials. Psychophysics in humans (n=23) revealed that half-sine stimulus durations >10 ms reduced detection thresholds, pain thresholds and stimulus current amplitudes required to generate a pain rating of 3 on an 11-point Numeric Rating Scale (NRS) as compared to 1 ms rectangular pulses (p<0.05). Increasing the duration from 1 to 25 ms led to a 4fold amplitude reduction for pain-thresholds and stimuli caused an axon-reflex flare. Excitability of single polymodal nociceptors in animals paralleled human psychophysics and we conclude optimized half-sine pulses facilitate C-nociceptor activation.

      Perspective

      Electrical stimulation with longer lasting half-sine wave pulses preferentially activates C-nociceptors and changes in the strength duration curve may identify nociceptor hyperexcitability in patients with neuropathic pain.

      Keywords

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