Preferential C-nociceptor stimulation facilitates peripheral axon reflex flare, but not secondary mechanical hyperalgesia.

"Silent" C-nociceptors are crucial for inducing 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 (HS) profile] whereas A-fibers are stimulated by 500 µs rectangular (R) pulses. We therefore expect 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 (NRS 6: HS 3.6 vs. R 9.2 mA, p = 0.001) and resulted in larger axon reflex erythema for high stimulus intensities (AUCFlare: NRS 6, 320.7 vs. 234.1 cm2⋅min, p = 0.015; NRS 3, 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 (NRS 6: r = 0.21, p = 0.036; NRS 3: r = 0.48, p = 0.0016). In contrast, the mean area of secondary mechanical hyperalgesia did not differ between HS and R [AUCHyper: NRS 6, 1,555 (HS) vs. 1,585 cm2⋅min (R), p = 0.893; NRS 3, 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. Clinical trial number: NCT0544026.