© 2012 John Wiley & Sons A/SClin Genet 2012: 82: 341–350
Printed in Singapore. All rights reserved

CLINICAL GENETICS
doi: 10.1111/j.1399-0004.2012.01943.x

Review

Nerve growth factor and the physiologyof pain: lessons from congenital insensitivity
to pain with anhidrosis
Indo Y. Nerve growth factor and the physiology of pain: lessons fromcongenital insensitivity to pain with anhidrosis.
Clin Genet 2012: 82: 341–350. © John Wiley & Sons A/S, 2012
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 andmaintenance 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 mediatorassociated with pain, itch and inflammation in adults. CIPA results fromloss-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 ofvarious 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 tointeroception, homeostasis and emotional responses and, together with thebrain, immune and endocrine systems, play crucial roles in pain, itch andinflammation. The NGF-TrkA system is essential for the establishment ofneural networks for interoception, homeostasis and emotional responses.
These networks mediate reciprocal communication between the brain andthe body in humans.
Conflict of interest

The author reports no conflict of interest.

Nerve growth factor (NGF) was the first growth factor
to be identified and characterized (1). NGF supports thesurvival and maintenance of peripheral neurons derived
from the neural crest and neurons in the brain during
embryonic development and in the early postnatal
stage. However, NGF also plays an important role in
inflammatory processes in adult animals (2–4).
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage.
Traditional animal studies of pain using electrophysiology, pharmacology and/or molecular biology haveyielded valuable insights into the molecular basis of

Y IndoDepartment of Pediatrics, Kumamoto
University Hospital, Kumamoto,
860-8556, Japan

Key words: CIP – CIPA – HSAN-IV –interoception – NGF-dependentprimary afferent neurons – NTRK1
gene – polymodal receptors – receptor
tyrosine kinase for NGF – sympathetic
neurons – TrkA receptor
Corresponding author: Dr YasuhiroIndo, Department of Pediatrics,
Kumamoto University Hospital, Honjo
1-1-1, Chuou-ku, Kumamoto
860–8556, Japan.
Tel.: +81 96 373 5191;
Fax: +81 96 373 5335;
E-mail: yindo@kumamoto-u.ac.jp
Received 30 May 2012, revised andaccepted for publication 23 July 2012pain perception (5–7). Genetic approaches using geneknockout mice have complemented these studies andcontributed to the study of pain pathways (8, 9). Pain
is a subjective and emotional experience, and it is often
difficult to evaluate this aspect of pain in animal studies. Experimental studies of pain involving humans as
subjects are usually not permitted due to ethical reasons.
Rare human genetic disorders provide opportunities
to explore pathological conditions in humans and theunderlying normal biological processes. In view of this,genetic variants leading to loss of pain have implications for pain medicine. Congenital insensitivity to pain

341

Indo
(CIP) includes several genetic disorders associated with
the inability to detect noxious stimuli. Patients with CIP
lack pain sensation. The molecular pathophysiology of
CIP can provide important clues about the biological processes of pain in our species and insights into
the mechanisms that underlie persistent or chronic pain
syndromes.
CIP is divided into two types: with anhidrosis (theinability to sweat) and without anhidrosis. Congenital
insensitivity to pain with anhidrosis (CIPA) is the firsthuman genetic disorder for which the molecular basisof CIP has been identified. CIPA is caused by loss-offunction mutations in the NTRK1 gene-encoding TrkA
(tropomyosin-related kinase A), a receptor tyrosine
kinase for NGF (10). Recent studies have identified thegenetic bases of other forms of CIP, including CIP due
to defects in NGF itself (11–13) and channelopathy
due to loss-of-function mutations in the SCN9A gene
(14–16).
It is well-known that NGF has two receptors: the p75
neurotrophin receptor (p75NTR ), a member of the tumor
necrosis factor receptor superfamily, and TrkA. p75NTR
is a low-affinity receptor for NGF and other neurotrophins, including brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4(17). p75NTR is involved in various mechanisms of
NGF-induced neural modulation. However, no human
genetic disorders attributable to loss-of-function mutations of p75NTR have been described thus far. This
review focuses on CIP due to genetic defects of NGF
and TrkA. The pathophysiology of CIP might provide
some clues to clarify the functions of the NGF-TrkA
system in humans.

SP
CC-1
LRMs
CC-2
NGF

Ig-1
Ig-2
TM
JX

P

P

TK

P

P

P

P

PLC-γ1Ras
Gab1
MAP kinase pathway

Neurite outgrowth

PI3-K

Survival and Growth

PKC

Ca2+

Synaptic plasticity

Fig. 1. Binding of nerve growth factor (NGF) to tropomyosin-related
kinase A (TrkA) receptors and intracellular signal transduction. The
binding of the NGF dimer to TrkA stimulates homodimer formation.
TrkA is phosphorylated in response to NGF and is essential for
intracellular signal transduction. The domain structure of TrkA with 790
or 796 amino acids is shown (23): SP, signal peptide; CC-1 and CC-2,
the first and second cysteine clusters, respectively; LRMs, leucine-richmotifs; Ig-1 and Ig-2, the first and second immunoglobulin-like motifs,
respectively; TM, transmembrane; JX, juxtamembrane; TK, tyrosine
kinase. A single-transmembrane domain divides TrkA into extracellularand intracellular domains. The extracellular domain is important for
specific NGF binding. The intracellular domain includes a tyrosine
kinase domain. Phosphorylated tyrosine residues – 490, 670, 674, 675
and 785 in the TrkA cytoplasmic domain – serve as anchors for binding
downstream signaling molecules (25). TrkA receptors control threemajor signaling pathways (17). The activation of Ras results in theactivation of the mitogen activated protein (MAP) kinase signalingcascade, which promotes neuronal differentiation, including neurite
outgrowth. The activation of phosphatidyl inositol-3-kinase (PI3-K)
through Ras or Gab1 promotes the survival and growth of neurons
and other cells. The activation of phospholipase C-γ1 (PLC-γ1) resultsin the activation of Ca2+ – and protein kinase C (PKC) – regulated
pathways that promote synaptic plasticity. Each of these signaling
pathways also regulate gene transcription.

NGF and its receptor tyrosine kinase, TrkANGF is initially synthesized as a proform of NGF(proNGF) that is cleaved to release the mature active
protein, NGF (17). The mature protein forms a stablenon-covalent dimer that is normally expressed atvery low levels during development. NGF mediates
biological effects by binding to and activating TrkA
receptors at nerve terminals (17). The activated TrkA
receptors then stimulate local effects at nerve terminals
and retrograde effects at neuronal cell bodies that often
reside at considerable distances from the terminals. The
major retrograde signal required for survival and gene
expression consists of activated TrkA itself.
The NTRK1 (also known as TRKA) gene was firstdetected and isolated in 1986 as a part of the trk
oncogene derived from human colon carcinoma (18,19). The physiological role of TrkA was then unveiled
when TrkA was shown to be the signaling receptor
for NGF (20, 21). Later, other members of the Trk
family were discovered and characterized. TrkB is thesignaling receptor for BDNF and NT-4, while TrkC is
the primary receptor for NT-3 (22). NT-3 also binds to
TrkA and TrkB, albeit with significantly lower affinity.
A single-transmembrane domain divides TrkA
proteins into extracellular and intracellular domains(Fig. 1) (22, 23). The extracellular domain is important342

for specific NGF binding and includes a signal
peptide, three tandem leucine-rich motifs flanked by
two cysteine clusters and two immunoglobulin-likedomains (or motifs). The intracellular domain includes
a juxtamembrane region, a tyrosine kinase domain anda very short carboxy-terminal tail. The intracellulardomain is phosphorylated in response to NGF andis critical for intracellular signaling. Phosphorylated
tyrosine residues in the TrkA cytoplasmic domain
serve as anchors for binding downstream signaling
molecules (22, 24). In vitro assessments have identified
TrkA tyrosine residues – 490, 670, 674, 675 and 785
as autophosphorylation sites (25).
The binding of NGF to TrkA stimulates homodimer
formation and tyrosine kinase activity (Fig. 1). TrkA
controls three major signaling pathways (17); NGF thus
regulates neuronal survival and apoptosis at several
levels. NGF functions as a survival signal and suppresses a cellular suicide program (apoptosis), while
deprivation of NGF activates cell death (26). The phosphatidyl inositol-3-kinase pathway induces suppressionof apoptotic proteins, while the mitogen-activated protein kinase pathway promotes neuronal differentiation,
including neurite outgrowth. NGF binding to TrkA
receptors also activates phospholipase C-γ (PLC-γ)

Nerve growth factor and the physiology of pain
in NGF-TrkA signal transduction lead to the failure ofsurvival of various NGF-dependent neurons since theseneurons are not maintained due to apoptosis during
development (44). As a result, patients with CIPA lack
all NGF-dependent neurons.
NGF-dependent primary afferent neurons with thinfibers (NGF-dependent primary afferents) are definedas primary afferent neurons with small diameters andthinly myelinated Aδ-fibers or unmyelinated C-fibersthat depend on the NGF-TrkA system during development (Fig. 3). The lack of pain and the presenceof anhidrosis in CIPA are due to the absence of
NGF-dependent primary afferents and sympathetic
postganglionic neurons, respectively.
Patients with CIPA most likely lack some neurons in
the brain, as these patients show mental retardation andcharacteristic behaviors. Patients with CIPA have mental retardation to variable degrees and exhibit learning
deficits. Affected children show defects in conceptual
thinking, abstract reasoning and social behavior andexhibit symptoms of moderate to severe emotional disturbance (45, 46). Hyperactivity and emotional lability
are common. Their behavior of children with CIPA isoften characterized as labile, hyperactive and erratic.
Conducting neuroanatomical studies of the forebrainsof patients with CIPA would be intriguing, though
no obvious gross abnormalities were recognized in
one patient examined more than four decades ago(47). Corresponding gene-knockout mice lack basal
forebrain cholinergic neurons (BFCNs) and striatal
cholinergic neurons (9). Neither BFCNs nor striatal
cholinergic neurons mature fully in knockout mice inthe absence of NGF/TrkA signaling (48). Therefore, it
is likely that patients with CIPA lack the corresponding
human neurons.

signaling pathways. PLC-γ signaling contributes to
NGF-mediated neural hypersensitivity (27). These signaling pathways probably contribute to the short-term
modulations of neurons such as increased amount (28,29) or phosphorylation (30) of ion channels in theplasma membrane and activation of other signaling
pathways (31). They are also important for the regulation of gene expression (32, 33).
Congenital insensitivity to pain with anhidrosis

CIPA is an autosomal recessive genetic disorder thatis characterized by insensitivity to pain, anhidrosis(the inability to sweat) and mental retardation. CIPAis also known as hereditary sensory and autonomic
neuropathy type IV (HSAN-IV) (34). Patients with
CIPA exhibit insensitivity to both superficial anddeep painful stimuli. Visceral pain perception is also
impaired. Touch, vibration and position senses arenormal. Motor functions are normal, although repeatedtrauma can induce secondary dysfunction in the motor
system. Sweating is important in order to maintainbody temperature, especially in humans – because
patients with CIPA do not sweat, they tend to develop
hyperthermia in hot environments.
CIPA results from loss-of-function mutations in
the NTRK1 gene (10, 35–43). The NTRK1 geneis located on chromosome 1q21-22. Examples of
NTRK1 mutations responsible for CIPA are shown in
Fig. 2. Patients with CIPA have no functional TrkA
proteins. NGF is a neurotrophic factor essential for thesurvival and maintenance of various types of neurons,
including primary afferent neurons with thin fibers,
autonomic sympathetic postganglionic neurons andpossibly several types of neurons in the brain. Defects

R654C
IVS6 +1G>C
Q176X

L213P

R508fs

D674Y
G577R

L93P

EXON

SP

CC-1

LRMs

4 5 6

7

CC-2 Ig-1

Y757X
R761W

[G613V][H604Y][R85S]

2 3

G715A

R602X

IVS7 +1G>A

1

G714S

L585 fs

Q308 fs
IVS7 -33T>AS131 fs

Q9X

G522R

Y359X

IVS4 -1G>C

R649W

R554 fs *IVS9 -1G>A

E164X

N67 fsV511fs

9 12
8 10 13
11 14
Ig-2 TM JX

D776 fs

IVS15 +3A>C

15 16 17

TK

Fig. 2. The location of human TRKA mutations associated with congenital insensitivity to pain with anhidrosis. The human TRKA gene, locatedon chromosome 1 (1q21-q22), is divided into 17 exons and 16 introns (83). The entire sequence is estimated to span at least 23 kb, coding fora protein of 790 or 796 amino acid residues. Six amino acid residues encoded by exon 9 are in the extracellular domain of the neuronal-specifictropomyosin-related kinase A (TrkA) receptor (84). The abbreviations on the bottom row indicate the domain structures (Fig. 1) encoded by thecorresponding exon(s) (23, 83). Multiple mutations were detected by our group and are shown here. The numbering system of the mutations after
exon 9 is different from that used previously (37–41). An asterisk denotes the common Japanese founder mutation (G554fs). The three variants inbrackets are probably polymorphisms in a particular ethnic background.

343

Indo
Immune cells

Temperature stressMechanical stress
Local metabolism
Cell rupture
Cutaneous parasite penetration
Mast cell activation
Immune and hormonal activity

CGRP
SP

NGF-dependent primary afferent
neurons with thin fibers

V

CGRP
SP

IX
X

Blood vessel

DRG
Piloerector muscle

Sweat gland

SG

STT

Sympathetic postganglionic neurons
Other target organs or tissues

Fig. 3. Patients with congenital insensitivity to pain with anhidrosis lack nerve growth factor (NGF)-dependent primary afferent neurons with thinfibers (NGF-dependent primary afferents) and autonomic sympathetic postganglionic neurons. NGF-dependent primary afferents are dorsal root
ganglia (DRG) neurons or trigeminal ganglia (V) neurons with free nerve endings. A subset of neurons in the glossopharyngeal nerve (IX) andthe vagus nerve (X) are most likely NGF-dependent neurons. Sympathetic postganglionic neurons innervate blood vessels, piloerector muscles andsweat glands as well as other target organs or tissues in the body. Postganglionic fibers to sweat glands are cholinergic. Triggering factors (shownby bold arrow) may directly or indirectly stimulate NGF-dependent primary afferents. Upon stimulation, these neurons release neuropeptides (SPand CGRP) that modulate inflammation, pain and itch. Sympathetic postganglionic neurons can also influence inflammation. CGRP, calcitonin
gene-related peptide; DRG, dorsal root ganglia; SG, sympathetic ganglion; SP, substance P; STT, spinothalamic tract. Adapted from Indo (62). This
figure is the author’s version of the manuscript (62) and is posted in the Kumamoto University Repository System (http://reposit.lib.kumamotou.ac.jp/handle/2298/23889).

BFCNs include neurons of the nucleus basalis of
Meynert, the medial septal nucleus and the verticaland horizontal nuclei of the diagonal band (Broca) (49,50). BFCNs are projection neurons, the axons of which
extend throughout the hippocampus and the neocortex,
and are important for learning, memory and, more
specifically, processes of attention (49, 51). Striatal
cholinergic neurons are large interneurons involved in
the control of movement. Recent studies of rodents
and humans suggest that the striatum is critical forthe procedural memory involved in forming behavioral
habits (52). The importance of cholinergic neurons
and NGF signaling in neurodegenerative diseases isalso well documented (53). Animal studies, as wellas human studies, indicate the existence of other
NGF-dependent neurons in the brain. Further studies
are needed to determine the functional significance of
these neurons.
Congenital insensitivity to pain due to mutationsof the NGFB gene
Norrbottnian congenital insensitivity to pain

A missense mutation in the NGFB gene-encoding NGF
protein has been detected in a large family from northern Sweden (11, 12, 54). In normal individuals, NGF isinitially synthesized as the proNGF and proteolytically344

processed and secreted as mature NGF (17). The
mutation in this family substitutes C to T at nucleotide
position 661 and changes a basic Arg to a non-polar
Trp at position 211 (R221W) in proNGF (or position
100 in the mature NGF protein). Expression studies ofthis mutant protein show markedly reduced secretion of
mature form; protein bearing this substitution is foundmainly in the form of proNGF (55, 56). Therefore,
decreases in the availability of mutant mature NGF andlosses of trophic support of NGF-dependent neurons
are most likely responsible for the phenotype of CIP
observed in this family.
Homozygous patients have a severe congenital formof the disease with onset of symptoms occurring at an
early age and most often affecting the lower extremities with insidious progressive joint swelling or painlessfractures (54). Arthropathy tends to be progressive,
resulting in disabling Charcot joints with gross deformities and instability. These patients lack deep pain
perception in bones and joints and have no protective
reflexes, which lead to gross bone and joint complications. They also show impaired temperature perception with normal sweating. No mental retardation isobserved. In contrast, heterozygous patients have mild
or moderate problems with joint deformities, usuallywith only slight discomfort (54). Some heterozygous
patients are without symptoms.

Nerve growth factor and the physiology of pain
Sural nerve biopsies from homozygous patientsshow severe reductions in the numbers of unmyelinated C-fibers and moderate losses of thin myelinatedAδ-fibers (54). Nerve biopsies from heterozygous
patients show moderate losses of both Aδ andC-fibers. Interestingly, the same results are seenin either symptom-free or neuropathic heterozygous
subjects.
Therefore, the phenotype of CIP in this family
is less severe than that of patients with CIPA. The
inheritance pattern of CIP in this family seems to
be autosomal dominant since either homozygous orheterozygous individuals show insensitivity to pain
to varying degrees. Individuals who are heterozygous
for the NGF mutation in this family show a milder
phenotype than homozygous individuals. This suggeststhat either there is a gene dosage effect for the R221W
mutation (12, 56) or the mutation might have a small
dominant-negative effect in heterozygotes (13) – forinstance, low levels of secreted R221W proteins may
interfere with wild-type NGF homodimerization, thus
resulting in reduced NGF function.
A loss-of-function mutation in the NGFB gene

A homozygous loss-of-function has been detected ina consanguineous Arab family in which five of the six
children are completely unable to perceive pain (13).
This mutation, c.[680C>A] + [681_682delGG], is a
C-to-A transversion at nucleotide 680 and a two basedeletion at nucleotide 681–681, causing a frame-shift at
amino acid valine 232 and the replacement of 15 aminoacids with a novel 43 amino acid terminal sequence(V232fs). The mutant gene produces precursor proteins
V232fs that have no biological activities.
Homozygous patients in this family are completely
unable to perceive pain and are mentally retarded.
They do not discriminate between temperatures nor
do they sweat. Consanguineous, heterozygous parents
have no clinical phenotype, do not report high pain
thresholds and have not suffered from any painlessinjuries or particular medical problems. The absence ofphenotype in the parents indicates autosomal recessive
inheritance of CIP in this family. Sural nerve biopsies
were not available.
The phenotype of the patients was categorized ashereditary sensory and autonomic neuropathy type V(HSAN-V) in the report (13). However, the classification of HSAN-V is controversial (57, 58). The characteristic phenotypes observed in patients with CIP fromthis family are similar to those observed in patientswith CIPA. This suggests that CIPA can be caused byloss-of-function mutations in the NGFB gene.
It is interesting to note that why CIPA in this Arabfamily includes mental retardation and anhidrosis
and Norrbottnian CIP does not. The reason might
be attributed to a complete defect of NGF proteinin this family, compared with a partial defect of thesame protein in Norrbottnian CIP, sparing mental
activity and sweating. Further studies are needed toclarify this.

Anatomy and functions of NGF-dependent neurons:lessons from CIPA
Interoception and polymodal receptors

NGF-dependent primary afferents innervate all tissuesof the body, including the skin, muscles, joints,
teeth and viscera, and have small diameters andconsist of thinly myelinated Aδ-fibers or unmyelinatedC-fibers (Fig. 3). The cell bodies of NGF-dependentprimary afferents are located in the dorsal root ganglia
alongside the spinal cord for the body or the trigeminal
ganglia for the face and have peripheral and central
axonal branches that innervate their target organs andspinal cord, respectively. A subset of neurons in
the glossopharyngeal nerve (IX) and the vagus nerve(X) are most likely NGF-dependent primary afferents
because visceral pain perception is impaired in patientswith CIPA. These afferent neurons in the IX and X
transmit visceral afferent information to the brain fromthe head and neck and from the thoracic and abdominal
cavities, respectively.
NGF-dependent primary afferents not only detectnoxious stimuli, but also transmit sensations from the
body’s interior, the so-called interoceptive sense (59,60). The interoceptive system is considered to be ahomeostatic afferent pathway representing the physiological status of all tissues of the body, including
the mechanical, thermal, chemical, metabolic and hormonal status of the skin, muscles, joints, teeth andviscera. NGF-dependent primary afferents are thus also
referred to as ‘interoceptive polymodal receptors’ (61,62). Interoceptive polymodal receptors show slow activities that transmit changes in a wide variety of physiological conditions, such as temperature, mechanicalstress, local metabolism (acidic pH, hypoxia, hypercapnea, hypoglycemia, hypo-osmolarity and lactic acid),
cell rupture (ATP and glutamate), cutaneous parasite
penetration (histamine), mast cell activation (serotonin,
bradykinin and eicosanoids) and immune and hormonal
activity (cytokines and somatostatin) (59, 60). Therefore, NGF-dependent primary afferents, i.e. interoceptive polymodal receptors – comprise both homeostaticafferent pathway and nociceptive pathway.
Sympathetic postganglionic neurons

Sympathetic postganglionic neurons are also
NGF-dependent neurons and innervate blood vessels, piloerector muscles and sweat glands in the skin
as well as other target organs and tissues in the body(Fig. 3). Sympathetic neurons regulate sweating in hot
environments and piloerection and vasoconstriction
in cold environments. Therefore, these neurons play
critical roles in the homeostasis of body temperature,especially in humans. Because patients with CIPA
do not sweat, they tend to develop hyperthermia in
hot environments and suffer from hypothermia incold environments. Clinical and behavioral studies
also suggest that patients with CIPA lack sympathetic
regulation of various target tissues, including internalorgans.

345

Indo
NGF-dependent neurons contribute to pain, itch andinflammation

Injury or tissue damage activating NGF-dependent primary afferents causes the sensation of pain (Fig. 3)
and activates sympathetic responses. These responses
are involved in various reactions that protect the body,
including withdrawal reflexes and vasoconstriction.
Upon stimulation, NGF-dependent primary afferents
release various neuropeptides [e.g. SP and calcitonin
gene-related peptide (CGRP)] that modulate inflammation, pain and pruritus (Fig. 3). In turn, these neuropeptides trigger the release of pro-inflammatory mediatorsthat amplify or facilitate inflammation by enhancing
vasodilation, blood flow, vascular leakiness and leukocyte trafficking to sites of inflammation (63).
Insect bites and invasion by parasites also activate
NGF-dependent primary afferents and cause itch sensations that create the desire to scratch the skin. Injury andmicrobial invasion stimulate the local release of numerous chemicals that mediate or facilitate inflammatory
processes (64, 65) and influence the expression of NGF.
Therefore, both pain and itch sensations are related to
local tissue damage and inflammatory responses.
Autonomic sympathetic nerves innervate various
cells in the body and thereby maintain homeostasis
and regulate inflammation and host defenses. Therefore, mediators derived from NGF-dependent primaryafferents or peripheral autonomic neurons, including
sympathetic postganglionic neurons, play important
regulatory roles in the body under many physiologicaland pathological conditions (62). Pain and itch sensations also provoke emotional responses in the brain
and contribute to the creation of memories surrounding
tissue-damaging events. It is likely that patients with
CIPA lack these neural processes.
NGF-dependent neurons and the brain, immune
and endocrine systems

The nervous, immune and endocrine ‘super-systems’
engage in multiple interactions in response to acuteand chronic stress (66, 67). The brain is the central
organ of stress, and the brain and immune system areessential for homeostatic regulation and survival (66).
The endocrine system is engaged in coordinating andcontrolling complex responses of the brain and immune
system (63, 66–68).
NGF-dependent neurons play critical roles in mediating cross-talk among these three ‘super-systems’(Fig. 4). NGF-dependent primary afferents detect andtransmit local changes associated with injury, tissue
damage and/or associated inflammatory or immunological reactions. These reactions include those involvedin the innate immune system (63, 65, 69). The systemic response of the sympathetic nervous system
to dangerous signals, including internal events suchas pain or external events such as threats, is also
well-known as the ‘fight-or-flight’ response. Interestingly, NGF-dependent sympathetic postganglionic neurons constitute a branch of the efferent sympathetic

346

Brain

Spinal

S

P
P

S

M

Body
ImmuneEndocrine

Fig. 4. Nerve growth factor (NGF)-dependent neurons and the brain,
immune and endocrine systems. NGF-dependent primary afferents(P) and sympathetic postganglionic neurons (S) form an interface
between the nervous system and the body and play critical roles
in mediating cross-talk between the three ‘super-systems’: the brain,
immune and endocrine systems. NGF-dependent primary afferents
report the physiological or pathological status of various tissues inthe body to the brain via the spinal cord, and the brain maintains
homeostasis in the body via sympathetic neurons and other autonomic,
neuroendocrine and behavioral mechanisms. Triggering factors (shownby bold arrow) may directly or indirectly stimulate NGF-dependentprimary afferents. Recursive loops of P from the body indicate signaltransduction via the axon reflex. The axon reflex is an efferent functionof the NGF-dependent primary afferents in which the release of
neuropeptides such as substance P and calcitonin gene-related peptide
affects functions in the body, e.g. blood vessels, mast cells (M) andvarious immune cells. Mast cells reside in various tissues and constitutea critical effector mechanism in inflammation. The systemic responseof the sympathetic nervous system to dangerous signals is known as
the ‘fight-or-flight’ response and activates the stress system in thebrain. The peripheral limbs of the stress system are located in theendocrine hypothalamic-pituitary-adrenal (HPA) axis and the efferent
sympathetic/adrenomedullary systems (68). The immune system canaffect the brain directly via cytokines in blood flow during inflammatory
responses (63, 65, 67, 68). In response to this, the brain affects
the immune system via NGF-dependent neurons and the HPA axis.
The parasympathetic portion of the autonomic nervous system also
plays an important role in the control of immunity and inflammation(not shown). The endocrine system is engaged via the HPA axis incoordinating and controlling complex responses of the brain and theimmune system. In accordance with the concept of ‘super-systems’,
NGF-dependent neurons are considered to form communication routes
between the brain, immune and endocrine systems.

system (Fig. 4). Indeed, patients with CIPA show theabsence of sympathetic skin responses (70) and low levels of plasma norepinephrine after thirst tests or during
surgical procedures (71). These results indicate that no
sympathetic reactions occur during stressful events inpatients with CIPA.
NGF-dependent primary afferents or sympathetic
postganglionic neurons influence inflammation by
secreting pro-inflammatory or anti-inflammatory substances into sites of inflammation (63, 65–69, 72, 73).
The term ‘neurogenic inflammation’ refers to signs ofinflammation (e.g. tumor, rubor, calor and dolor) thatdevelop upon the activation of neurons and the consecutive release of a neuronal mediator (74). The axonreflex is an efferent function of the NGF-dependent primary afferents (Fig. 3). Indeed, patients with CIPA lackthe axon reflex responsible for neurogenic inflammation. This suggests that neurogenic inflammation does
not occur without NGF-dependent neurons.

Nerve growth factor and the physiology of pain
It would be worthwhile to mention here the importance of mast cells in the brain, immune and endocrine
systems (Fig. 4). The mast cell is a resident cell invarious tissues and is a critical effector cell for inflammation. Mast cells are located perivascularly, close to
NGF-dependent neurons containing neuropeptides suchas SP and CGRP (67–69).In response to injury or
tissue damage, bradykinin, a peptide that stimulates
these neurons, is produced, causing pain sensations (4).
Mast cells also release various inflammatory mediators, including histamine, serotonin and eicosanoids in
response to bradykinin. Various inflammatory mediators
derived from mast cells induce inflammation and also
stimulate NGF-dependent neurons.
Mast cells can contribute to multiple features ofacute, chronic and allergic inflammation (69, 75). In
allergic inflammation, inflammatory mediators derived
from mast cells stimulate NGF-dependent primaryafferents of the nose, skin and airways, resulting insneezing, itching and coughing (75). Therefore, mast
cells are ideally equipped and placed to integrate
and relay signals from all three super-systems during
peripheral tissue responses to psychological or pathological stress (67, 69).
NGF acts as a peripheral pain mediator, particularly during inflammatory pain states, in adults (2,4). The expression of NGF is high in injured andinflamed tissues and is upregulated in a wide variety of inflammatory conditions (2, 76, 77). NGF is
an important component of the chemical milieu of
inflammation (7). The activation of TrkA receptors on
NGF-dependent neurons triggers and potentiates pain
signaling through multiple mechanisms (78). The sensitization of NGF-dependent neurons by inflammation or
NGF contributes to the development of hypersensitivity
in neighboring tissues.
Patients with CIPA lack NGF-dependent neurons
and therefore they probably cannot mediate various
neural or inflammatory processes via these neurons
in the brain, immune and endocrine systems. Again,
these patients are at a disadvantage, as the lack of
critical neural and inflammatory processes threatens
survival. In accordance with the concept of ‘supersystems’, NGF-dependent neurons are considered tobe communication routes between the brain, immune
and endocrine systems. The NGF-TrkA system thus
contributes to the establishment of neural networks in‘super-systems’.
NGF-dependent neurons and emotional responses

NGF-dependent neurons, i.e. primary afferents andautonomic sympathetic postganglionic neurons, form
an interface between the nervous system and the
body-proper (Fig. 5). Most information from thebody is conducted to the brain unconsciously andthe brain maintains homeostasis in the body via
feedback mechanisms for which autonomic sympathetic
neurons are indispensable. This is well illustrated by(unconscious) homeostatic control of body temperature.

Brain

Inputs to APG

STTSpinal cord

SG

DRG or TG

S

P
Body-proper

Fig. 5. Nerve growth factor (NGF)-dependent neurons mediate
reciprocal communication between the brain and the body-proper.
NGF-dependent neurons constitute a part of the neural network forinteroception and homeostasis and play important roles in emotions
and adaptive behaviors. The diagram is a schematic presentation of
the transmission signals that occur between the body-proper and thebrain via NGF-dependent neurons, including NGF-dependent primaryafferents (P) (interoceptive polymodal receptors) and sympathetic postganglionic neurons (S). The body-proper refers to the organism minus
the neural tissues (the central and peripheral components of the nervous system). NGF-dependent primary afferents are DRG neurons ortrigeminal ganglia (TG) neurons with free nerve endings. The trigeminal nerve carries sensory information from the face, sinuses, teeth andthe anterior portion of the oral cavity. Axons of the trigeminal nerve
ganglion cells that process pain and temperature sensations terminate
in the spinal nucleus of the trigeminal nerve. A subset of neurons
in the glossopharyngeal nerve and the vagus nerve are most likely
NGF-dependent neurons (not shown). APG, autonomic preganglionic
neurons; DRG, dorsal root ganglia; SG, sympathetic ganglion; STT,
spinothalamic tract.

In humans, systemic responses of the sympathetic
nervous system often accompany emotional responses.
When humans are exposed to danger or trauma,
stimuli or contexts associated with the danger ortrauma become learned triggers that unleash emotional
responses (79, 80). From birth, normal individuals
experience emotions such as fear whenever they are
exposed to danger or trauma in daily life. Theseemotional experiences then induce so-called ‘fear
conditioning’ by pairing the stimuli or contexts withdanger or trauma. Therefore, emotional responses
serve a protective role by producing aversion tocontexts associated with danger. Due to their lack of
NGF-dependent neurons, patients with CIPA cannot
detect various noxious stimuli nor trigger emotional
responses to noxious stimuli in the same way as normal
individuals. Accordingly, they may be impaired in theirability to modify their behaviors in order to protect
their bodies and maintain homeostasis.
Emotion is a strong feeling characterized by various complex reactions with both mental and physicalmanifestations closely related to activities of the sympathetic nervous system. The ‘fight-or-flight’ response
illustrates a strong emotional state associated with an

347

Indo
extreme excitation of the sympathetic nervous system.
Normal individuals, however, experience emotion tovarying degrees in daily life. Most emotional responses
occur at levels beneath awareness.
Extreme emotions may have a deleterious effect on
health and daily life. Antonio Damasio proposed (81)that emotions are in the loop of reason, and that emotion
may assist rather than disturb reasoning processes.
Damasio further advanced a hypothesis (known as
the ‘Somatic Marker Hypothesis’) that emotions andfeelings play critical roles in decision-making via
mechanisms he termed ‘somatic markers’(81); he uses
the term ‘emotions’ to denote a collection of changes
occurring in both the brain and body that are usuallyprompted by particular mental contents (81). Feelings
are the perceptions of these changes. According to thishypothesis, somatic markers tag neural images involved
in reasoning processes with emotions related to pastexperiences, thereby conferring differential values uponsuch images. The human brain uses these somatic andemotional signals to make decisions that conform topreviously acquired knowledge.
It is interesting to note that the autonomic nervous
system is crucial to achieving the appropriate modification of physiological parameters in the body thatgenerate somatic state that characterizes certain emotions. Indeed, sympathetic skin conduction responses
have been used as indices to test the Somatic Marker
Hypothesis in the laboratory (81). Damasio also proposed that interoceptive polymodal receptors convey
internal milieu and visceral signals from the body’s
interior to the brain and play critical roles in feelings (82). NGF-dependent neurons mediate reciprocal
communication between the brain and the body-proper(Fig. 5). Therefore, these neurons play important rolesin the structures and behaviors underlying the SomaticMarker Hypothesis.
Conclusion

Genetic studies have revealed that CIPA results fromloss-of-function mutations in the NTRK1 gene encoding
the receptor tyrosine kinase for NGF. This showsthat the NGF-TrkA system plays a crucial role in thedevelopment and functions of nociceptive reception andthe establishment of thermoregulation via sweating inhumans. CIPA can also serve as a model to determine
the mechanisms of survival and maintenance of NGFdependent neurons in the autonomic, sensory andcentral nervous systems and the functions of theseneurons in humans. The molecular pathophysiologyof CIPA strongly suggests that the NGF-TrkA systemis essential for the establishment of peripheral neuralnetworks involved in the interoception and homeostasis
that may also underlie certain emotions.
Recent studies indicate that NGF-dependent neurons
play crucial roles in brain–immune–endocrine interactions in pain, itch and inflammation and suggest that the
NGF-TrkA system is involved in various disease states.
Targeting the molecular mechanisms of NGF-TrkA signal transduction is an active area of research that may

348

help to develop novel analgesics and anti-pruritic andanti-inflammatory drugs.
Acknowledgements
This work was supported in part by the Japan Society for
the Promotion of Science (JSPS) (KAKENHI) Grant-in-Aid for
Scientific Research and by the Ministry of Health, Labour andWelfare: Health and Labour Science Research Grants (Researchon Intractable Diseases).

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