Evidence for frequency-dependent neuronal "wind-up" origin of temporal summation of pain - an experimental crossover investigation.

Abstract

Repetitive noxious stimulation can increase perceived pain intensity, a phenomenon known as Temporal Summation of Pain (TSP), thought to reflect central sensitization via neuronal "wind-up" in the spinal cord. As neuronal wind-up occurs only at stimulation frequencies above 0.2&#x202f;Hz, we have tested whether TSP also appears at two different frequencies using our recently developed TSP protocol in healthy volunteers. In a randomized crossover design, 30 healthy male participants (27&#xb1;4 years) underwent two experimental sessions involving 90 repetitive heat stimuli applied to the forearm at individually determined pain tolerance temperatures. Stimuli were delivered using a thermode at either 0.4 or 0.15&#x202f;Hz. Pain intensity was rated using a computerized visual analog scale (0-100). TSP was assessed via linear mixed-effects model (LMM), with pain intensity as the dependent variable. All participants finished the study. LMM revealed a significant main effect of stimulation frequency (<i>F</i> _{1, 540}=14.20, p&lt;0.001), indicating TSP. Pain intensity was higher at 0.4&#x202f;Hz compared with 0.15&#x202f;Hz (&#x3b2;=14.77, 95&#x202f;% confidence intervals (CI) 6.87-22.68, p&lt;0.001). The presence of TSP at 0.4&#x202f;Hz but not at 0.15&#x202f;Hz aligns with previous findings on neuronal wind-up, supporting its reliance to central sensitization. These findings enhance our understanding of the physiological basis of TSP and offer a robust platform for future investigations into pain modulation and therapeutic intervention strategies.