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

OBJECTIVES: 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 Hz, we have tested whether TSP also appears at two different frequencies using our recently developed TSP protocol in healthy volunteers. METHODS: In a randomized crossover design, 30 healthy male participants (27±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 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. RESULTS: =14.20, p<0.001), indicating TSP. Pain intensity was higher at 0.4 Hz compared with 0.15 Hz (β=14.77, 95 % confidence intervals (CI) 6.87-22.68, p<0.001). CONCLUSIONS: The presence of TSP at 0.4 Hz but not at 0.15 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.