Slow depolarizing stimuli differentially activate mechanosensitive and silent C nociceptors in human and pig skin

Pain, vol. 161, pp. 2119–2128

Abstract

ABSTRACT: High-threshold mechanosensitive and mechanoinsensitive ("silent") nociceptors have similar electrical thresholds for transcutaneous sine wave stimulation at 4 Hz that selectively activates cutaneous C nociceptors in human skin. Their fundamentally different functions particularly in chronic pain warrant differential stimulation protocols. We used transcutaneously delivered slow depolarizing stimuli (half-sine, 500 ms duration, 0.01-1 mA) in humans to assess intensity-response relations for the induction of pain psychophysically and recorded activation of mechanosensitive and silent nociceptors in healthy volunteers by microneurography. Differential C-fiber activation was confirmed in single-fiber recordings in pig allowing for stimulation amplitudes up to 10 mA. Perception and pain thresholds to half-sine wave pulses were 0.06 ± 0.03 mA and 0.18 ± 0.1 mA, respectively, and caused pain in an amplitude-dependent manner (n = 24). When matched for pain intensity, only sine wave stimulation induced an instant widespread axon reflex erythema (n = 10). In human microneurography, half-sine stimulation activated mechanosensitive nociceptors (n = 13), but only one of 11 silent nociceptors. In pig skin, the amplitude-dependent activation of mechanosensitive nociceptors was confirmed (0.2-1 mA, n = 28), and activation thresholds for most silent nociceptors (n = 13) were found above 10 mA. Non-nociceptive low-threshold mechanosensitive C fibers (n = 14) displayed lower activation thresholds for half-sine wave stimuli with an amplitude-dependent discharge increase between 0.01 and 0.1 mA. We conclude that transcutaneous electrical stimulation with 500-ms half-sine wave pulses between 0.2 and 1 mA causes amplitude-dependent pain by preferential activation of mechanosensitive C nociceptors.

Authors 8

1. Roman Rukwied

   Heidelberg University · Medizinische Fakultät Mannheim

   Affiliation as printed

   Department of Experimental Pain Research, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany

   Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article

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2. Otilia Obreja

   Heidelberg University · Medizinische Fakultät Mannheim

   Affiliation as printed

   Department of Experimental Pain Research, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany

   Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article

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3. Fiona Werland

   Heidelberg University · Medizinische Fakultät Mannheim

   Affiliation as printed

   Department of Experimental Pain Research, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany

   Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article

   Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com)

4. Inge Petter Kleggetveit

   Oslo University Hospital

   Affiliation as printed

   Section of Clinical Neurophysiology, Department of Neurology, Oslo University Hospital, Oslo, Norway,

   Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article

   Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com)

5. Ellen Jørum

   Oslo University Hospital · University of Oslo

   Affiliation as printed

   Department of Neurology, Oslo University Hospital, University of Oslo, Rikshospitalet, Oslo, Norway

   Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article

   Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com)

6. Richard W. Carr

   Heidelberg University · Medizinische Fakultät Mannheim

   Affiliation as printed

   Department of Experimental Pain Research, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany

   Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article

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7. Barbara Namer Aachen Research group Neuroscience Interdisciplinary Center for Clinical Research (IZKF) Medical Faculty

   Friedrich-Alexander-Universität Erlangen-Nürnberg · RWTH Aachen University

   Affiliation as printed

   Department of Physiology and Pathophysiology, University of Erlangen-Nuremberg, Erlangen, Germany

   Research group Neuroscience, Interdisciplinary Center for Clinical Research, Medical Faculty RWTH University, Aachen, Germany

   Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article

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8. Martin Schmelz corresponding

   Heidelberg University · Medizinische Fakultät Mannheim

   Affiliation as printed

   Department of Experimental Pain Research, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany