NGF enhances electrically induced pain, but not axon reflex sweating

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/m2, 20 Hz: 9 mL/h/m2, 100 Hz: 10 mL/h/m2). 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.