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ORIGINAL RESEARCH article
Front. Pain Res.
Sec. Neuropathic Pain
Volume 6 - 2025 | doi: 10.3389/fpain.2025.1556429
Preferential C-nociceptor stimulation facilitates peripheral axonreflex flare, but not secondary mechanical hyperalgesia
Provisionally accepted- 1 University Hospital of Basel, Basel, Switzerland
- 2 University of Mannheim, Mannheim, Baden-Württemberg, Germany
Silent" C-nociceptors are crucial to induce the axon reflex erythema in humans and may also contribute to spinal sensitization such as secondary hyperalgesia. Electrical slow depolarizing stimulation paradigms activate unmyelinated C-fibers (25 ms half-sine profile; HS) whereas Afibers are stimulated by 500 µs rectangular (R) pulses. We therefore expected to provoke larger areas of axon-reflex flare (silent nociceptor activation) and secondary hyperalgesia to HS stimuli.We compared axon reflex erythema and secondary mechanical hyperalgesia areas induced by intracutaneous electrical HS and R stimuli using stimulation intensities that induced pain ratings of 3 and 6 on a numeric rating scale (NRS 0-10) in 24 healthy volunteers.Slowly depolarizing C-fiber stimulation was linked to lower current intensities required to induce pain (NRS6: HS 3.6 vs. R 9.2 mA, p = 0.001) and resulted in larger axon reflex erythema for high stimulus intensities (AUCFlare: NRS6: 320.7 vs. 234.1 cm2⋅min, p = 0.015; NRS3: 79.1 vs. 51.0 cm2⋅min, p = 0.114). Preferential C-fiber stimulation indicated a correlation of axon reflex erythema with the areas of secondary mechanical hyperalgesia (NRS6: r = 0.21, p = 0.036; NRS3: r = 0.48, p = 0.0016).In contrast, mean area of secondary mechanical hyperalgesia did not differ between HS and R (AUCHyper: NRS6: 1555 (HS) vs. 1585 cm2⋅min (R), p = 0.893; NRS3: 590 (HS) vs. 449 cm2⋅min (R), p = 0.212) albeit it developed faster during HS.Our data confirm that silent nociceptors provoke the axon reflex erythema, but their role in secondary hyperalgesia appears to be less crucial.
Keywords: Hyperalgesia, C-fibers, Flare, Chronic Pain, electrical nerve stimulation
Received: 06 Jan 2025; Accepted: 28 Feb 2025.
Copyright: © 2025 Daneffel, Rukwied, Schmelz, Ruppen and Schneider. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Luana Daneffel, University Hospital of Basel, Basel, Switzerland
Tobias Schneider, University Hospital of Basel, Basel, Switzerland
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