Maximum axonal following frequency separates classes of cutaneous unmyelinated nociceptors in the pig

• Published in: The Journal of physiology 2021-03, Vol.599 (5), p.1595-1610
• Main Authors: Werland, Fiona, Hirth, Michael, Rukwied, Roman, Ringkamp, Matthias, Turnquist, Brian, Jorum, Ellen, Namer, Barbara, Schmelz, Martin, Obreja, Otilia
• Format: Article
• Language: English
• Subjects: Animals; axon; Axons; C‐fibre; discharge frequency; Electric Stimulation; excitability; Growth factors; Inflammation; Mechanical properties; Mechanical stimuli; Nerve Fibers, Unmyelinated; Nerve growth factor; Nociceptors; Pain; Pain perception; Saphenous nerve; sensitization; Skin; Swine
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/JP280269

Key points C‐nociceptors are generally assumed to have a low maximum discharge frequency of 10–30 Hz. However, only mechano‐insensitive ‘silent’ C‐nociceptors cannot follow electrical stimulation at 5 Hz (75 pulses) whereas polymodal C‐nociceptors in the pig follow stimulation at up to 100 Hz without conduction failure. Sensitization by nerve growth factor increases the maximum following frequency of ‘silent’ nociceptors in pig skin and might thereby contribute in particular to intense pain sensations in chronic inflammation. A distinct class of C‐nociceptors with mechanical thresholds >150 mN resembles ‘silent’ nociceptors at low stimulation frequencies in pigs and humans, but is capable of 100 Hz discharge and thus is suited to encode painfulness of noxious mechanical stimuli. Using extracellular single‐fibre recordings from the saphenous nerve in pig in vivo, we investigated peak following frequencies (5–100 Hz) in different classes of C‐nociceptors and their modulation by nerve growth factor. Classes were defined by sensory (mechano‐sensitivity) and axonal characteristics (activity dependent slowing of conduction, ADS). Mechano‐insensitive C‐nociceptors (CMi) showed the highest ADS (34% ± 8%), followed only 66% ± 27% of 75 pulses at 5 Hz and increasingly blocked conduction at higher frequencies. Three weeks following intradermal injections of nerve growth factor, peak following frequency increased specifically in the sensitized mechano‐insensitive nociceptors (20% ± 16% to 38% ± 23% response rate after 72 pulses at 100 Hz). In contrast, untreated polymodal nociceptors with moderate ADS (15.2% ± 10.2%) followed stimulation frequencies of 100 Hz without conduction failure (98.5% ± 6%). A distinct class of C‐nociceptors was exclusively sensitive to strong forces above 150 mN. This class had a high ADS (27.2% ± 7.6%), but displayed almost no propagation failure even at 100 Hz stimulation (84.7% ± 17%). Also, among human mechanosensitive nociceptors (n = 153) those with thresholds above 150 mN (n = 5) showed ADS typical of silent nociceptors. C‐fibres with particularly high mechanical thresholds and high following frequency form a distinct nociceptor class ideally suited to encode noxious mechanical stimulation under normal conditions when regular silent nociceptors are inactive. Sensitization by nerve growth factor increases maximum discharge frequency of silent nociceptors, thereby increasing the frequency range beyond their physiological limit, which pos