Congenital insensitivity to pain with anhidrosis (
CIPA) is an autosomal recessive
genetic disorder characterized by insensitivity to
pain,
anhidrosis (the inability to sweat) and
mental retardation.
Nerve growth factor (
NGF) is a well-known
neurotrophic factor essential for the survival and maintenance of
NGF-dependent neurons, including primary afferent neurons with thin fibers and sympathetic postganglionic neurons, during development.
NGF is also considered to be an inflammatory mediator associated with
pain, itch and
inflammation in adults.
CIPA results from loss-of-function mutations in the NTRK1 gene-encoding TrkA (
tropomyosin-related
kinase A), a
receptor tyrosine kinase for
NGF. Defects in
NGF-TrkA signal transduction lead to the failure of survival of various
NGF-dependent neurons. As a result, patients with
CIPA lack
NGF-dependent neurons. Recent studies have revealed that mutations in the NGFB gene-encoding
NGF protein also cause
congenital insensitivity to pain. Using the pathophysiology of
CIPA as a foundation, this review investigates the ways in which
NGF-dependent neurons contribute to interoception, homeostasis and emotional responses and, together with the brain, immune and endocrine systems, play crucial roles in
pain, itch and
inflammation. The
NGF-TrkA system is essential for the establishment of neural networks for interoception, homeostasis and emotional responses. These networks mediate reciprocal communication between the brain and the body in humans.