A tonic electrocutaneous stimulation paradigm for graded sensory C-fiber engagement in healthy subjects

Long-term pain models provide valuable proxies for studying physiological changes associated with chronic pain, which is commonly associated with sustained C-fiber-mediated nociceptive input and central sensitization, and are particularly useful in therapeutic and drug development research. We investigated tonic electrocutaneous stimulation (ECS), a method that enables precise temporal control and adjustable intensity within safe limits, using a 5 Hz sine-wave waveform intended to bias sensory responses toward C-fibers-mediated activity.

Twenty-one participants underwent three levels of personalized, 60-second ECS delivered at parameters intended to bias sensory responses toward C-fiber-mediated activity, three levels of short-term ECS using parameters commonly associated with Aδ-fiber-mediated responses, and mild long-term ECS using parameters commonly associated with Aβ-fiber-mediated activity as a non-painful control, skin conductance response (SCR) and level (SCL), continuous self-reported visual analog scale (VAS) pain ratings were recorded simultaneously.

The low-, medium-, and high-intensity ECS conditions produced statistically distinct self-reported pain scores and differentiable sympathetic nervous system (SNS) activation patterns in SCR and SCL. Compared to the non-painful control, low-intensity C-fiber-biased ECS did not differ in pain perception or SNS activity, whereas medium and high intensities elicited significantly greater responses. Repeated-measures correlation analysis revealed very strong associations between VAS scores and stimulus intensity across the entire stimulation period (r ≥ 0.90, p<.001). Both SCR and SCL exhibited fair correlation coefficients throughout stimulation (r = 0.35-0.58, p<.05), while SCL correlations declined to poor, non-significant levels after first 30 seconds (r = -0.05-0.22, p = n.s.).

Our proposed model provides a controllable and reproducible approach for inducing long-term, intensity-dependent pain in human subjects, offering a physiologically relevant experimental paradigm with high temporal precision.