Targettissue Sensoryneuron CNS

Local cells
Odontoblast
Fibroblast
Dendritic
Vascular
Schwann
Immune
Stimuli
Mechanical
Thermal
Chernical
Inflammatory
Fig 7-3 Dentinal, pulpal, and periodontal innervation 01 a mature erupted
tooth are shown here. The labeled dentinal zones (A, B, C, and D) on the left
side 01 the tooth have been found to have more than 40% 01 dentinal tubules
innervated at the tip of the pulp horn; nerve density decreases progressively
Irom midcrown to cervical dentin to the root3,6 The panels on the right show
differences in pulpodentin organization and nerve incidence in the crown and
the root, BV, blood vessels; DC, dendritic cel!; N, nerve; F,fibroblast; 0, odontoblasts;
D, dentin; E, enamel; 4, location of the image in Fig 7-4; 5, location 01 the
images in Fig 7-5. (Modified from Byers and Narhi4 with permission.)
contributes different kinds of somatosensory
information needed for integrated oral function
and tissue preservation during tooth use, For
example, the gingiva provides sensations of touch,
pressure, and temperature via activation of special
mechanoreceptors or tb e rrnor e ce p to rs . The
junctional epithelium is richly innervated by sensory
fibers that release neuropeptides to regulate
vasodilation, transmigration of leukocytes across
the epithelium into the oral cavity, and antimicrobial
actions. The periodontal ligament contains many
large Ruffini mechanoreceptors from the trigeminal
ganglion or mesencephalic nucleus that give
sensations of tooth touch and occlusal plane location
Axonal transport slgnals

'1-400 mm/day I
Central
anterograde _ •.
~Retrograde

Ir'"50--,"oo-m-m-/d-ay"l
CNS neurons
5
during chewing, speech, and swallowing,26-29 Some
part of the sensory information from the periodontal
mechanoreceptors may remain unconscious and
serve automatic reflex responses needed for the
regulation of the masticatory functions. AII the
orofacial tissues also have a variety of nociceptive
fiber types, including polymodal nociceptive nerve
fibers (eg, silent nociceptors) that initiate acute pain
sensation or trigger iriflammatory pain, as discussed
later in this chapter in the section on human teeth,
Together, the multiple nerve fiber systems of these
regions provide an integrated regulatory system that
acts on teeth and their supporting tissues.
135
Dental /nnervation and /ts Responses to Tooth /njury
Fig 7-4 Various sizes of myelinated A-fiber axons and unmyelinated
(-fiber bundles are visible in this cross section of a nerve that
has just ente red the root of a mouse molar. The A fibers include many
large A¡3 myelinated and medium or small Aa myelinated axons (bar
= 0.01 mm)
Fig 7-5 Light microscopic autoradiography of nerve endings in dentin. (a) About half of
the tubules in the inner dentin (D) of this dog tooth have autoradiographic labeling indicating
the location of trigeminal nerve endings. PD, predentin (bar = 0.1 mm). (Modified from
Byers et allO with permission.) (b) Autoradiographically labeled trigeminal nerve endings in
an adult rat molar are concentrated in the tubular dentin (D) while avoiding the atubular
reparative dentin (RD). The predentin (PD) is wider at the innervated regions than it is for
other crown dentin (bar = 0.065 rnrn), (Modified from Byers et al" with permission.) (e) A
highly branched single Aa ending is shown here for the crown dentin (D) and pulp of a rat
molar. Its terminal branches (arrow) extend into the odontoblastic layer (O) and dentinal
tubules (bar = 0.01 mm). (Modified from Byersl2 with permission.)
Fig 7-6 (a) Odontoblasts (OB) connected by gap junctions (b/aek dais) that
are associated with beaded peptidergic intradentinal innervation (red fibers)
and large nerve endings that end clase to odontoblasts on the dentin side of
their gap junctions and in the predentin portions of dentinal tubules (green
fibers and endings). Approximate pasitions for the electron micrographs
are shown (b lo e). (b) Preterminal axons in the plexus of Raschkow from a
human tooth. AII have los) myelin and some are clase to each other (arrows)
without a Schwann cell sheath (bar = 0.001 mm). (Modified from Byers et
alll with permission.) (e) This nerve-like fiber (N) in ahuman tooth maintains
a separation from the adjacent odontoblast process (OP) (bar = 0.005 mm).
(Modified from Frankl4 with permission.) (d) An autaradiographically labeled
trigeminal fiber (N) is separated by a small, uniform space (arrow) from an odontoblast, as well as from other nerve-like fibers, in a rat molar
(bar = 0.005 mm). (Modified
from Byersl5 with permission.) (e) This dentinal tubule from ahuman tooth contains two nerve-like processes (N) that maintain their separation
(arrow) from the odontoblast
process (OP) in that region of the terminal fiber (bar = 0.005 mm). (Modified from Byers et alll with permissian.)
d
The sensory innervation of teeth includes
hundreds of branches from each of the incoming
e
myelinated A or unmyelinated fibers (Figs 7-4 and
7-5). Most of the A fibers terminate in the coronal
odontoblastic layer, predentin, and inner dentin
136
e
(Figs 7-5 and 7-6), while most fibers end in the
pulp and along pulpal blood vessels. The biggest
axons, the A¡3 fibers, make large endings near
odontoblasts along the dentin-pulp border near
the pulp horn tip and lack the receptors for the lowGeneral
Aspects of Dental Innervation
Fig 7-7 Trigeminal ganglion dental nerve cell bodies, labeled with
tracers from rat molars. (a) Radioactive glial-derived neurotrophic
factor (GDNF) (white dots) was transported back from rat molars
to large neuronal cell bodies in the trigeminal gangljon (bar =
0.05 mm). (Reprinted from Kvinnsland et al" with permission.) (b)
Radioactive nerve growth factor (NGF) molecules (black dots) are
transported retragradely to large and medium cell bodies in the
trigeminal ganglion within 15 hours (bar = 0.05 mm). (Modified from
Wheeler et al44 with permission.) (e) Red dye (D-I) was transported
from an injured molar to the cell body in trigeminal ganglion and
is associated with a glial injury reaction (Iighl green) in its satellite
cell. Nearby satellite cells of uninjured neurons are also reacting by
expressing glial fibrillary acidic protein (Gfap) (dark green) (bar =
0.05 mm). (Reprinted from Stephenson and Byers45 with permission.)
affinity nerve growth factor (NGF) receptor." They
are the fibers that are most sensitive to mechanical
(hydrodynamic) stimulation of dentin.v" The large
endings of these A¡3 fibers make close appositions
with odontoblasts (see Fig 7-6), and individual fibers
can contact a group of neighboring cdontoblasts."
The majority of A fibers are small and medium
myelinated fibers, many of which contain the neuropeptide
calcitonin gene-related peptide (CGRP)
and express receptors for NGP6 (see Figs 7-4 to 7-6).
Most of these innervate dentin, predentin, and the
odontoblastic layer in the coronal regions underlying
enameI.3.4.12 The dentinal endings occur close to the
odontoblast processes. No synaptic or gap junctions
have been found for nerve-odontoblast associations,
but a paracrine signaling mechanism would be facilitated
by close association without cellular or matrix
barriers between them (see Fig 7-6).
Most of the Aa innervation is concentrated in
dentin near the pulp horn tip; it is progressively
less frequent toward the cervical region and least
prevalent in the root dentin. Thus, there are focal
regions of dense innervation of dentin oriented
toward the occlusal contact zones and specific
gradients of innervation. There are also some slowconducting
thin Aa fibers (see Fig 7-4) that have
capsaicin sensitivity." as discussed later. Finally, at
least half of the nerve fibers in human teeth are
unmyelinated, slow-conducting C fibers" (see below).
During development, there is close coordination
between the maturation of pulp and dentin and the
arrival and maturation of sensory innervation that
relies heavily on discrete expression of neurotrophin
growth factors39.40 AII dental nerve fibers seem
to require an NGF-dependent staqe." but in the
adult, a major component of dental innervation is
regulated by glial cell line-derived neurotrophic
factor (GDNF),42while the rest of the fibers retain their
NGF dependence'" (Fig 7-7).That organization is also
found elsewhere throughout the body; the GDNFdependent
group mainly has mechanosensitive
functions, and the NGF-dependent adult fibers
have polymodal or ndciceptive sensitivity as well as
paracrine signaling via release of neuropeptides. An
additional special feature of dental innervation is
that all fibers continue to express growth-associated
protein (GAP-43) in the adult, unlike similar fibers
in other tissues, such as skin46 Thus, the mature
sensory innervation of teeth is continually adjusting
its position in relation to the status of the pulpodentin
cornplex so that important cytochemical changes
continue to occur throughout the life of the tooth39.43
Additional details about molecular subspecializations
within the A¡3, Aa, and C nerve fibers are
still being discovered, especially in relation to the
ion channels and membrane receptors that regulate
their functions."? as described in the section on
human teeth and in chapter 8.
137
Dental Innervatian and Its Respanses to Tooth Injury
Sympathetic and
Parasympathetic Innervation
of Teeth
The vasodilatory functions of sensory innervation
in teeth are opposed by the vasoconstricting activity
of the sympathetic fibers9,14,47 (see chapter 6).
The sympathetic fibers are much less numerous
than the sensory fibers, although there are differences
among species in those relative proportions.
Sympathetic fiber distribution also differs from that
of sensory fibers in that the sympathetic fibers are
located mainly in deeper pulp and along blood vesseis.
Parasympathetic activity can affect blood flow in
teeth, but it is not clear whether that activity derives
from intradental or periodontal sites. In any case, the
relative importance of parasympathetic activity is
much less than that of sympathetic activity for regulation
of pulpal homeostasis and blood flow. These
autonomic functions counterbalance the vasodilation
produced by sensory nerve fibers, as discussed
in detail in chapter 6.
Role of Odontoblasts in Tooth
Sensation
Odontoblasts are complex cells that regulate dentinogenesis
and its maintenance, set up barriers
between dentin and pulp, help regulate blood flow
and dentinal fluid, and have antimicrobial defense
and immune functions." In addition, odontoblasts
are closely associated with nerve fibers of the pulpodentin
complex, and much current work concerns
their possible involvement in sensitivity of teeth.
Their lack of synaptic or gap junction connections
with the nerve fibers ' suggests that they do not have
primary sensory functions. Subsequent technologies
have shown profuse cytochemical paracrine signaling
in teeth that greatly expanded the possibilities
for neuromodulating actions by odontoblasts" or by
other pulp cells23 as well as expanding the range of
pulpal responses to neural factors (Box 7-1).
Demonstrations of neural-like ion channels'? and
TREK-1, a mechanosensitive potassium channel.'?
in odontoblasts show that they are excitable and
mechanosensitive cells, as does their expression
138
B 7-1 I Some agents involved in
ox neuropulpal interactions*
Neural agents that affect pulp cells and blood vessels
• Sensory neuropeptides: CGRP,substance P,neurokinin A,
somatostatin, galanin
• Sensory neurotransmitters: glutamate, acetylcholine
• Autonomic factors: norepinephrine, peptide histidine
isoleucine, acetylcholine, neuropeptide Y
• Schwann cell factors: NGF,GDNF,neurotrophin receptors
Dentinal, pulpal, vascular, or immune agents that
affect dental nerve function
• Odontoblast-specific molecules
• Neurotrophic factors: NGF,brain-derived neurotrophic
factor, GDNF
• Inflammatory mediators: serotonin, histamine, bradykinin,
prostanoids, cytokines
• Cellular breakdown products: adenosine triphosphate,
cyclo-oxygenase, oxidative radicals
• Altered pH and its excitation or inhibition of molecular
functions
• Heat shock proteins
• Somatostatin and endocrine factors
• Antinociceptive agents (eg, opioid peptides, cannabinoids,
adenosine)
• Extracellular matrix factors (eg, laminin and
metalloproteinases)
• lonic environment
• Oxygen tension and interstitial fluid pressures
• Bacterial agents
"Neural" factors expressed by pulp
• Neurotensin, nestin, protein gene product 9.5
• Tachykinin precursor and receptor
• Neurotrophin receptors: tyrosine kinase A, p75
• Neurotrophins: NGF,brain-derived neurotrophic factor,
GDNF
• Nitric oxide
• Neural-like calcium, sodium, and potassium channels
* See text for references about neuropulpal interactive signaling.
of a variety of voltage-gated ion chanriels." In
addition, they actively attract nerve fibers " and
express neurotrophin factors and receptors
in development and after injury39,42,50 Pulp stem
cells can even acquire neural-like functions under
special conditions.v'-v Recent work shows that
keratinocytes directly affect neural activity and
nociceptive sensitization in skin,53 and odontoblasts
may similarly influence events that make teeth hurt.
Those mechanisms in normal teeth would change
during pulpitis. Recent efforts to define neuropulpal
interactions are discussed further in the section on
human teeth later in this chapter.
Structural and Cytachemical Respanses to Iootn Injury and Infectian
Structural and Cytochemical
Responses to Tooth Injl:lry and
Infection
Reactions inside teeth
Injury to the pulpodentin complex causes neuronal
responses that vary for different types of fibers and
along a time spectrum from milliseconds to weeks
or rnonths.v-'? The nerve fibers not only send rapid
electrophysiologic signals to the ganglion and central
pain pathways but also release neuropeptides
and other agents from their peripheral terminals
that regulate vasodilation and leukocyte invasion of
the injury site and affect every local cell type; this
includes themselves via autocrine actions. In addition,
they pick up and transport local pulp factors
such as NGF that convey information about pulp
status to the neuronal cell body.
The dental sensory fibers react to tooth injury
by extensive anatomical and cytochemical changes
in their preterminal branches and endings. In rat
models of dental injury, there is an initial depletion
of neuropeptides followed by an increase in neuropeptide
content and sprouting of the terminal fibers
within 1 day after injury. Those responses differ in
intensity and duration depending on the severity of
the injury9,1O,14,54 Innocuous stimuli such as vibration
may cause nerve fibers to be activated at levels sufficient
to cause changes in neurally regulated pulpal
homeostasis, blood flow, and interstitial fluid pressure
(see chapter 6).
Stimuli that injure the pulpodentin complex have
been classified at four different levels.4 Type I injuries
are least damaging. They cause a transient change
in pulp, sometimes including reactive dentinogenesis
(the original odontoblasts survive and are not
replaced by reparative cells). There is extensive
sprouting of neuropeptide-rich nerve fiber endings
near the injury that return to normal within a
few days to a few weeks. Those changes have been
correlated with local production of NGF by the
fibroblasts near the injury site44,55 Under these conditions,
there is little or no invasion of leukocytes,
and the local defense mechanisms are sufficient.
Examples of this type of injury are shallow cavity
preparations, shallow scaling of cervical dentin, and
strong orthodontic forces.
Type 11injuries have more extensive dentinal injury
with some loss of pulp tissue and focal inflammation.
Invasion of leukocytes and local vascular responses
occur, but the pulp can repair itself and form reparative
dentin. For these lesions, there is extensive
sprouting of sensory fibers that have enhanced neuropeptide
contents such as CGRP and substance P.
Examples of this type of injury include deep dentinal
cavities, small pulpal exposures, and heat stimulation
of long duration and/or high intensity.
For these intermediate injuries, the sprouting
and CGRP upregulation continue as long as there
is active inflammation that has not been walled off
by scar formation (Fig 7-8). During aging of teeth,
the pulp narrows, the innervation is reduced, and
the nerve fibers contain fewer neuropeptides.V
While those changes may alter the ability of teeth
to defend against pathogens or injuries, a study of
dentinal cavity injury in old rats found the same ability
for sprouting responses as in the younger teeth.58
Type 111injuries cause enough pulpal damage and
infection that local repair is not possible, and irreversible
pulpitis ensues." If a tooth has been denervated
prior to injury,59the extent of damage is greater
and the progression to necrosis proceeds more
quickly (Figs 7-9a and 7-9b). Some of the conditions
that lead to irreversible pulpitis are large infected
pulpal exposures, bacterial invasion at failed restorations,
deep infected caries, failure of pulp to make
a scar barrier around an abscess, and coronal pulp
destruction by heat or other excessive stimulation.
An increased intensity of sensory nerve sprouting
in the surviving pulp near the lesion correlates with
elevated pulp cell expression of NGF after dentinal
injury. In contrast, both NGF expression and sensory
sprouting are low at sites of healing (see Fig 7-8c).
Type IV injuries involve other tissues in addition
to dentin and pulp. These situations occur
when pulpal infections expand out of the tooth
into the periradicular tissues to affect ligament and
bone56,6Q(Figs 7-9c t07-ge). Periodontal tissues are
also involved at the time of initial injury in a variety of
dental fractures. In addition, tooth extractions damage
the ligament, and pulpotomy can cause longterm
nerve reactions in the periradicular tissue."
139
Dentallnnervation and Its Responses to Tooth Injury