Nerve growth factor (NGF) modulates sensitivity and sprouting of nociceptors. We explored the spatial and temporal sensitization induced by NGF injection (1 microg) in human skin. Hyperalgesia was investigated in 16 volunteers (36+/-9 years) at day 1, 3, 7, 21, and 49. Areas of mechanical (brush, pin-prick) and heat (43 degrees C) sensitization were mapped and thermal (heat and cold) pain thresholds, mechanical (impact stimulation) and electrically evoked pain, and axon reflex flare were assessed. No spontaneous pain or local inflammation was recorded upon NGF injection and during 49 days. Sensitization to heat was maximum at day 3 and lasted 21 days. Hyperalgesia to cold was recorded at day 7 and 21. Hypersensitivity to mechanical impact stimuli developed delayed, reached maximum at day 21, and persisted throughout 49 days. Fifty percent of all volunteers reported a static allodynia to tonic pressure until day 21. Electrical stimulation at 7.5 mA was more painful at the NGF site at day 21, which correlated significantly to maximum impact pain. Axon reflex flare was unaffected by NGF. Sensitization was limited to the NGF injection site, no touch- or pin-prick evoked secondary hyperalgesia was observed. Spatially restricted hyperalgesia indicates a peripheral rather than central mechanism. The temporal profile of lasting nociceptor sensitization suggests an altered peripheral axonal expression of sensory proteins specifically leading to mechanical and thermal sensitization. Intradermal NGF administration provokes a pattern of sensitization that can be used as experimental model for neuropathic pain.

High-affinity receptors for nerve growth factor (NGF) are found on nociceptors and sympathetic efferents. NGF is known to sensitize nociceptors, increase innervation density, and fire frequency of sympathetic fibers. We explored axonal sensitization of afferent and efferent fibers following intracutaneous injection of NGF in human and pig skin. In humans, frequency-dependent (5, 20, 100 Hz) electrically induced pain was assessed 1, 3, 7, 21, and 49 days post injection. Sweat output was recorded in parallel using the quantitative sudomotor axon reflex test (QSART). Electrically induced pain ratings (7.5 mA for 30 s) significantly increased at the NGF sites for 5 Hz (numeric rating scale [NRS] 6±0.5 vs 3.7±0.4), 20 Hz (NRS 7.2±0.4 vs 5±0.5), and 100 Hz stimulation (NRS 6.9±0.4 vs 5.4±0.3) at day 21, and also for 5 Hz at day 49 (NRS 5.4±0.4 vs 3.8±0.3). Electrically evoked QSART increased frequency dependent, but was not altered by NGF throughout the entire observation period (average QSART at 5 Hz: 3 mL/h/m(2), 20 Hz: 9 mL/h/m(2), 100 Hz: 10 mL/h/m(2)). Similarly, NGF did not change the activity-dependent slowing of conduction of sympathetic efferents (6±2% vs 5.1±1.5%, for 3 minutes, 2 Hz) in pig single-fiber recordings. In parallel to the increased pain ratings recorded in humans, activity-dependent slowing of mechano-insensitive nociceptors was reduced by NGF (18.1±2% vs 29±1.4%). In summary, axonal sensitization of nociceptors by NGF could underlie the hyperalgesia to electrical stimulation. Enhanced responses were limited to nociceptors, as no sensitization was found in sympathetic efferent neurons.

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