Nerve growth factor (
NGF) is a powerful trophic factor that provides essential support for the survival and differentiation of sympathetic and sensory neurons during development. However,
NGF also activates nociceptors contributing significantly to inflammatory
pain and
neuropathic pain after tissue injury. As such anti-
NGF based
therapies represent a promising strategy for
pain management. Because of dose-dependent serious side effects such as
back pain, injection site
hyperalgesia, clinical trials of using
NGF to treat various disorders such as
diabetic neuropathies,
chemotherapy-induced and human immunodeficiency virus-associated
peripheral neuropathies were all discontinued. Thus far, worldwide clinical applications of
NGF in treating patients are very limited except in China. Hereditary sensory autonomic neuropathy type V (
HSAN V) is an extremely
rare disease. Genetic analyses have revealed that
HSAN V is associated with autosomal recessive mutations in
NGF. One of the mutations occurred at the 100th position of mature
NGF resulting in a change of residue from
arginine to
tryptophan (R100W). Although those
HSAN V patients associated with the NGFR100W mutation suffer from severe loss of deep
pain,
bone fractures and joint destruction, interestingly patients with the NGFR100W mutation do not show apparent cognitive deficits, suggesting important trophic support function is preserved. We believe that NGFR100W provides an ideal tool to uncouple the two important functions of
NGF: trophic versus nociceptive. Studies from investigators including ourselves have indeed confirmed in animal testing that the NGFR100W no longer induced
pain. More importantly, the trophic function seemed to be largely preserved in
NGF harboring the R100W mutation. On the mechanistic level, we found that the NGFR100W mutation was capable of binding to and signaling through the
tyrosine receptor kinase A receptor. But its ability to bind to and activate the 75 kDa
neurotrophic factor was significantly diminished. The significance of these findings is at least two folds: 1) the NGFR100W mutation can be used as an alternative to the wildtype
NGF to treat human conditions without eliciting
pain; and 2) the 75 kDa
neurotrophic factor may serve as a novel target for
pain management. We will discuss all the details in this mini-review.