NGF induces non-inflammatory localized and lasting mechanical and thermal hypersensitivity in human skin

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.