ArticleThe Journal of physiology2026
No evidence for homotopic hyperalgesia to C fibre stimulation after transcutaneous high-frequency stimulation in humans.
Article in The Journal of physiology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
In humans transcutaneous high-frequency electrical stimulation (HFS) has been reported to increase pain elicited by single electrical stimuli at the HFS-treated site, an effect thought to represent the perceptual correlate of homosynaptic long-term potentiation (LTP) at spinal C fibre synapses. However this finding has not been consistently replicated. In previous studies hyperalgesia has been commonly assessed using rectangular electrical pulses, which may not sufficiently activate C fibre nociceptors. In two preregistered experiments we investigated whether 4 Hz sinusoidal electrical stimulation, which has been shown to reliably activate C fibres, elicits homotopic hyperalgesia after HFS in healthy human volunteers. In both experiments transcutaneous HFS was applied to one of the two forearms, resulting in enhanced pinprick sensitivity in the adjacent skin. In experiment 1 (N = 26) participants received 60 s of 4 Hz sinusoidal stimulation at 0.2 mA before HFS and at 10, 30 and 50 min afterwards on each arm. The repeated-measures ANOVA on the pain ratings before HFS and at 50 min after HFS revealed no significant interaction between time and arm. To address the possibility that the 4 Hz stimulation given before HFS may have prevented the induction of hyperalgesia, and to enhance C fibre recruitment, a second experiment was conducted (experiment 2, N = 28). Participants received 60 s of 4 Hz sinusoidal stimulation at 0.7 mA, 50 min after HFS on each arm. The Bayesian paired t test provided moderate evidence against a difference in pain ratings between the two arms. Taken together we found no evidence for homotopic hyperalgesia to C fibre stimulation after HFS. KEY POINTS: High-frequency electrical stimulation (HFS) of peripheral nociceptors produces homosynaptic long-term potentiation (LTP) at spinal C fibre synapses in animals. 4 Hz sinusoidal electrical stimulation preferentially activates C fibres. We found no evidence for hyperalgesia to the 4 Hz stimulation after HFS in humans.
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