Sustained nerve growth factor-induced C-nociceptor sensitization to electrical sinusoidal stimulation in humans

Abstract

Introduction: Injection of recombinant human nerve growth factor (rhNGF) evokes acute heat and prolonged “polymodal” (mechanosensitive [CM]) and “silent” (mechanoinsensitive [CMi]) C-nociceptor sensitization. Both nociceptor classes can be activated differentially using slowly depolarizing electrical sinusoidal stimuli. Objectives: To explore the temporal profile of nociceptor sensitization to heat and mechanical and electrical stimuli in humans after rhNGF. Methods: Recombinant human nerve growth factor (1 µg) and NaCl (0.9%) was injected into human forearm skin (n = 9, 50 µL/injection). Pain ratings (numeric rating scale) to transcutaneous electrical stimuli (1 ms 20 Hz rectangular pulses, 500-ms half-period sine wave [1 Hz] and 4 Hz sine wave pulses [2.5 and 60 seconds]) were assessed at days 3, 21, and 49 after injection, in addition to heat pain thresholds (HPTs, 9 × 9 mm thermode) and mechanical impact pain (4 and 8 m/second). Results: Suprathreshold sinusoidal stimulation for specific CM (1 Hz) and combined CM and CMi (4 Hz) activation resulted in enhanced pain from day 3 post rhNGF and lasted throughout 7 weeks. These temporal dynamics contrasted minimum HPTs at day 3 (normalized by day 49) or mechanical impact pain (developing slowly until day 21 before declining depending on stimulus intensity). Correlation analyses of electrical pain indicated diverging kinetics when assessed for CM with or without concomitant CMi activation at days 3 and 21, which converged 7 weeks post rhNGF. Conclusions: Exceptionally long sensitization of CM and CMi nociceptors by rhNGF, uncovered by suprathreshold electrical sinusoidal stimulation, indicates a signal transduction–independent long-lasting hyperexcitability of C-nociceptors that clinically may contribute to rhNGF-maintained chronic inflammatory pain.