Optimum electrical sinusoidal frequency stimulation to activate C-nociceptors

Introduction: Electrical sinusoidal stimulation has been shown to reliably activate C-fibers. Here, we explored the optimum sinusoidal frequency for C-nociceptor responses. Objectives: Identify the optimum sinusoidal frequency to activate single C-nociceptors in pigs and to provoke pain and axon reflex flare in humans. Methods: Single C-fibers (n = 60) were recorded from pig saphenous nerves in vivo in response to transcutaneous sinusoidal electrical stimulation delivered at frequencies of 3 to 100 Hz with increasing amplitudes. In 22 human subjects, 30 sinusoidal pulses were delivered with 3 to 20 Hz at 0.0125 to 0.4 mA amplitudes and perception thresholds, evoked pain (numeric rating scale, 0–10) and axon reflex flare (full-field laser perfusion imaging) were monitored in 4 seconds intervals. Results: Single C-nociceptors (36 “polymodal” [C-mechano-heat-sensitive], 15 “very high threshold, and 9 “silent” [C-mechano-insensitive]) were activated more easily at frequencies below 8 Hz as compared with frequencies >10 Hz. In humans, pain and flare responses were also found to be frequency dependent. Pain threshold assessments were particularly sensitive at a frequency of 4 Hz. Highest pain ratings were recorded from 3 to 6 Hz at stimulation amplitudes of 0.2 mA. Significant axon reflex flare responses developed at low amplitudes of 0.05 and 0.1 mA at frequencies of 4 and 8 Hz only. Conclusion: Sinusoidal frequencies between 3 and 8 Hz are better suited to activate C-nociceptors than stimuli above 10 Hz and are expected to facilitate C-nociceptor recruitment for their functional assessment in volunteers and chronic pain patients.