Although
nerve growth factor (
NGF) is a well-known
neurotrophic factor, it also acts as a mediator of
pain, itch and
inflammation.
Congenital insensitivity to pain with anhidrosis (
CIPA) is an autosomal recessive
genetic disorder caused by loss-of-function mutations in NTRK1, the gene encoding a
receptor tyrosine kinase for
NGF, TrkA. Mutations in NTRK1 cause the selective loss of
NGF-dependent neurons in otherwise intact systems.
NGF-dependent primary afferents are thinly myelinated Aδ or unmyelinated C-fibers that are dependent on the
NGF-TrkA system during development. In
CIPA, the lack of
pain and the presence of
anhidrosis (inability to sweat) are due to the absence of both
NGF-dependent primary afferents and sympathetic postganglionic neurons, respectively. These peripheral neurons form an interface between the nervous system and the 'body-proper' and play essential roles in the interoception and sympathetic regulation of various tissues or organs. Patients with
CIPA also show
mental retardation and characteristic behaviors and are probably neuron-deficient within the brain. However, the functions of
NGF-dependent neurons in the brain are controversial, both in animal and in human studies. This review focuses on various brain regions that express TrkA
mRNA, based on data from the Allen Human Brain Atlas, and discusses putative neuronal networks related to these brain regions in humans. A better understanding the distribution of
NGF-dependent neurons in the brain will provide a framework for further studies to investigate
pain, interoception and emotional responses. Furthermore, strategies targeting the molecular mechanisms through which the
NGF-TrkA system functions may provide hope for the development of novel
analgesics.