The neurotrophin Nerve Growth Factor (NGF) sensitizes nociceptors, by increasing the response to noxious stimuli. The relationship between NGF and pain is supported by genetic evidence: mutations in the NGF TrkA receptor in patients affected by an hereditary rare disease (Hereditary Sensory and Autonomic Neuropathy type IV, HSAN IV) determine a congenital form of severe pain insensitivity, with mental retardation, while a mutation in NGFB gene, leading to the aminoacid substitution R100W in mature NGF, determines a similar loss of pain perception, without overt cognitive neurological defects (HSAN V).

Here we show that the R100 mutation selectively alters binding to p75NTR and some of the signaling pathways activated downstream of TrkA NGF receptors. NGFR100 mutants maintain identical neurotrophic and neuroprotective properties in a variety of cells and in vivo animal models, while displaying a significantly reduced pain-inducing activity in vivo. These results, while contributing in clarifying which receptors and intracellular signaling cascades participate in the pain sensitizing action of NGF, set the basis for the development of new NGF mutants with potential clinical applications.