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

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.

Nerve growth factor sensitizes nociceptors to C‐fibre selective supra‐threshold electrical stimuli in human skin

“…In addition to traditional threshold measures, assessment of C‐nociceptor electrical excitability may broaden the characterization of hypersensitivity in chronic pain patients. Here, we investigated sensitization of C‐nociceptor sub‐classes to NGF using electrical sinusoidal stimulation paradigms (Jonas et al., 2018; Rukwied et al., 2020). We found enhanced axonal excitability of mechano‐sensitive C‐nociceptors to 1 Hz (500 ms half sine) stimulation.…”

“…Intradermal injection of NGF is known to facilitate action potential generation and conduction (Obreja, et al., 2011; Obreja et al., 2018; Rukwied et al., 2014). In order to induce action potential discharge preferentially in nociceptors we designed an electrode (Landmann et al., 2016) and a stimulus profile (Rukwied et al., 2020) to specifically depolarize mechano‐sensitive C‐nociceptors. A half sine wave constant current stimulus provokes a burst of action potentials (Rukwied et al., 2020) and we found that NGF increased the pain ratings to the most intense amplitude of half sine wave stimulation.…”

“…In order to induce action potential discharge preferentially in nociceptors we designed an electrode (Landmann et al., 2016) and a stimulus profile (Rukwied et al., 2020) to specifically depolarize mechano‐sensitive C‐nociceptors. A half sine wave constant current stimulus provokes a burst of action potentials (Rukwied et al., 2020) and we found that NGF increased the pain ratings to the most intense amplitude of half sine wave stimulation. In DRG neuronal somata, maximum evoked discharge frequency to depolarizing voltage steps vary considerably between different classes of primary afferent neurons (Zheng et al., 2019).…”

“…The authors identified a distinct constellation of voltage‐gated ion‐channels in various populations of sensory afferents that could underlie the unique discharge properties recorded upon depolarization (Zheng et al., 2019). Notably, low‐intensity half sine wave electrical stimuli also activated low‐threshold mechano‐sensitive (LTM) C‐fibres (Rukwied et al., 2020) but did not evoke any sensation. We therefore conclude that LTMC‐fibres are less likely to contribute to enhanced pain responses following NGF.…”

“…One profile (500 ms half sine) preferentially activates mechano‐sensitive C‐nociceptors with increasing discharge frequencies at higher current intensities (Rukwied et al., 2020). The other (4 Hz sinusoidal) stimulates mechano‐sensitive and mechano‐insensitive (‘silent’) C‐fibres in synchrony with the sinusoidal cycle (Jonas et al., 2018; Rukwied et al., 2020) and leads to pronounced accommodation of pain upon sustained application (Jonas et al., 2018). Notably, this accommodation in healthy subjects is absent in the symptomatic skin of neuropathic pain patients (Jonas et al., 2018).…”