Endodontic Topics 2010, 17, 1241 2010 r John Wiley & Sons A/S

All rights reserved ENDODONTIC TOPICS

1601-1538

Inflammatory nerve responses in

the dental pulp
INGE FRISTAD, ATHANASIA BLETSA & MARGARET BYERS

Tooth pulp has a dense innervation and a rich vascular supply to maintain homeostasis and to preserve the integrity
of the tissue. Function, trauma, and antigenic challenges make teeth and supporting tissues susceptible to tissue
injury and inflammation, partially due to the lack of collateral blood and nerve supply and to their low compliance.
This review focuses on dental nerve functions and adaptive changes in the pulpal nerve supply following
inflammation and peripheral injury. Overviews of dental innervation and its development and of the peptidergic
innervation of oral tissues are presented, followed by a discussion of peripheral and central changes after local insults
to teeth and peripheral nerve injuries. The functional implications of these adaptive changes are considered.

Received 13 February 2009; accepted 3 September 2009.

Innervation of teeth and supporting
tissues
Sensory nerves: The trigeminal nerve, with neurons
located in the trigeminal ganglion, provides the sensory
supply to the oral tissues, including teeth and supportive
structures. The trigeminal nerve emerges from the ventral
surface of the pons, near its upper border. This cranial
nerve has three divisions: the ophthalmic, the maxillary,
and the mandibular branch. The maxillary and mandib-
ular branches innervate the upper and lower jaws,
respectively. The neurons supporting the upper and lower
teeth are organized in distinct locations in the ganglion
(Fig. 1). Sensory innervation of periodontal tissues also
comes from the trigeminal mesencephalic nucleus (1, 2).
Autonomic nerves: The autonomic innervation of
the pulp and periodontium can be subdivided into
sympathetic and parasympathetic nerves, although the
presence, origin, and distribution of the latter are
controversial and still debated. Post-ganglionic sympa-
thetic nerve fibers innervating oral tissues originate
from the superior cervical ganglion (SCG) (Fig. 1).
Developmental aspects
Tooth development and innervation
Teeth, like many other organs, develop as a result of
epithelialmesenchymal interactions, governed by signal-
ing molecules in a spatial and time-dependent manner
(3). Teeth are well-defined peripheral target organs, and a
highly sophisticated neural system is required for both
their function and protection. Dental trigeminal axon
growth and patterning are tightly linked to advancing
tooth morphogenesis and cell differentiation. The dental
nerve fibers reach the tooth germ during a period of
programmed cell death within the trigeminal ganglion
neurons. During this period, the survival of the neurons is
dependent on growth factors supported by the target
field (4). Several studies, both in human and murine
teeth, have shown that axon growth and patterning take
place in a spatio-temporally controlled manner, tightly
linked with advancing tooth morphogenesis (510).
Innervation of dentin takes place during early tooth
development (8, 1113). At the start of root formation in
rat teeth, the pioneer sensory fibers are already approach-
ing the odontoblast layer and dentin in the regions where
the largest amount of dentin is formed (8, 1113).
Neurotrophins in tooth development,
maturation, and aging
When innervation commences, the nerve growth
factor (NGF) concentration in the tooth pulp is high,
but it declines afterwards (14). NGF therefore seems to
play an important role in the establishment of pulpal
innervation, since a reduced number of both sympa-

12

Fig. 1. Sensory nerves to teeth and supporting tissues
originate from the trigeminal ganglion (TG). Post-
ganglionic sympathetic nerve fibers innervating oral
tissues originate from the superior cervical ganglion
(CSG). Max, maxillary area; Mand, mandibulary area.
thetic and sensory axons has been found after admin-
istration of NGF-antibodies to neonatal rats (15). The
pulpal sensory nerves are found to express the nerve
growth factor receptor p75 (p75NGFR) and tyrosine kinase
A (TrkA) (13, 1619), that bind all known neurotrophins
with low affinity (20, 21). In addition, TrkB receptor of
the high-affinity group, binding brain-derived neuro-
trophic factor and neurotrophin-3 (NT-3) (20, 22), is
shown to be expressed by sensory nerves during tooth
development (23). Few, if any, pulpal afferents express the
high-affinity NT-3 receptor TrkC (18). From recent
research, different neurotrophins have been connected
to the development of different neuron types, and hence
to the development and survival of the different fiber types
(24). The discovery of receptors sensitive to a number of
growth factors in teeth and supporting tissues indicates
that these growth-promoting signals may be involved in
the regulation of nerve in-growth, and like NGF (25, 26),
these growth factors are expressed in a spatial and temporal
manner in developing and mature teeth (2730) (Fig. 2).
There is a considerable anterograde axonal transport in
dental sensory fibers (12, 3138), including neuropep-
tides and cytoplasmatic components (Fig. 3). There is
also a robust retrograde axonal transport (39), which
includes an active uptake of neurotrophic factors (15,
27, 4042) and transport from peripheral target tissues
to the cell body (27, 4345) (Fig. 4).
Neurotrophic and target-derived factors regulate
neuronal structure, survival and function, and are
Inflammatory nerve responses
Fig. 2. Nerve growth factor (NGF) synthesis is retained
in adult teeth, especially in subodontoblast coronal pulp,
and is up-regulated after injury. NGF-mRNA is up-
regulated in the mesial pulp horn 6 h after cavity
preparation (asterisk). Reprinted with permission from
Taylor & Francis Ltd. (30).
important for the maintenance of neuronal phenotype
characteristics. During development, all dental fibers
appear to require NGF and TrkA at some stage (46),
whereas in adult teeth, the large trigeminal neurons are
potentially dependent only on dental pulp-derived glial cell
line-derived neurotrophic factor (GDNF) while small
dental trigeminal neurons seem to be dependent on NGF
(27, 47). This suggests that GDNF may function as a
neurotrophic factor for subsets of nerves in the tooth,
which apparently mediate mechanosensitive stimuli (Fig.
4), whereas NGF is suggested to support neurons res-
ponsible for nociception (48). This phenomenon is found
throughout the peripheral nervous system (4951), and
has gained substantial support since the discovery of NGF
(52). NGF is the most extensively investigated among the
trophic factors that mediate target support of neurons
(53), and has come to be widely used as a model in the
study of neurotrophic factors (54). Binding of target-
derived NGF is dependent on specific receptors located on
the axonal surface, with subsequent internalization and
transport to the cell body, where the effects are mediated.
The retrograde and anterograde axoplasmatic trans-
port systems represent bi-directional communication
between the neuron and the peripheral target organ,
and can be utilized in tracing studies to establish
peripheral and central projections of axons and nerve
endings (11, 15, 29, 3137, 39, 5560) (Fig. 5). The
neurotoxic drug capsaicin (an extract from red pepper),
acting on vanilloid receptors expressed on sensory C
fibers (6062), has been reported to destroy the micro-
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Fristad et al.

Fig. 3. Trigeminal pulpal nerve fibers labeled by anterograde axonal transport of protein labeled with 3H-proline. Nerve
fibers branch in crown and innervate peripheral pulp and inner dentinal tubules of dog (A) and rat (B) teeth. Reprinted
with permission from Alan R. Liss Inc. (37, 38).

Fig. 4. Glial cell line-derived neurotrophic factor (GDNF) is produced in the dental pulp (A). Radioactive labeled
GDNF injected into the dental pulp is transported to neurons in the trigeminal ganglion by retrograde transport. GDNF
is found in a subset of nerves which apparently mediate mechanosensitive stimuli (B and C). OMR, ophthalmic-maxillary
region; BT, brain tissue (control); D, dentin; O, odontoblast layer; P, pulp; G, gingiva. Courtesy of Dr. I. Hals
Kvinnsland. Reprinted with permission from Blackwell Munksgaard (27).

14

Fig. 5. Tracing and characterization of pulpal neurons in the trigeminal ganglion. A trigeminal ganglion section labeled
with d-opioid receptor (DOR) antibody (A) and pulpal neurons retrogradely labeled with Fluorogold (FG) (B).
Reprinted with permission from Elsevier (60).
tubule system, thus resulting in the blockage of both the
afferent and efferent axoplasmatic transport (63, 64).
Although neurotrophins and their receptors are
expressed in a spatial and time-dependent manner
during tooth development (13, 23, 25, 29), several
studies have shown that the neurotrophic property of
the pulp is retained and may also be up-regulated in
mature teeth (13, 23, 27, 30, 65) (Fig. 2).
The peptidergic nerves
The discovery of neuropeptides as transmitters and sig-
naling molecules has given new insight into neurobiology
and the function of the peripheral nerves, including the
structure and function of the nerve fibers in the pulp
dentin complex. The neuropeptide first demonstrated in
the dental pulp was substance P (SP) (66), a member of
the tachykinin family. Since then a large number of
neuropeptides including calcitonin gene-related peptide
(CGRP), neurokinin A (NKA), neuropeptide Y (NPY),
vasoactive intestinal polypeptide (VIP), and somatostatin
has been demonstrated immunohistochemically, and their
origin, occurrence, and spatial distribution in teeth
and supporting tissues have been studied and mapped
(8, 6676).
Inflammatory nerve responses
Origin, axonal transport, and distribution
Sensory nerves
There are at least six distinct types of dental sensory nerve
fibers based on physiology: A-b, A-d-fast, A-d-slow, and
three kinds of C-fibers (17, 70, 71, 7793). Neuropep-
tides including CGRP (Fig. 6) and peptides of the
tachykinin group, such as SP and NKA, are synthesized
on ribosomes in the cell body of sensory neurons (94,
95). They are transported both centrally and in the
peripheral axons. The first evidence for axonal transport
of sensory neuropeptides came from immunohistochem-
ical data 30 years ago for sensory fibers in general (96)
and for dental axons in particular (66). The overall
average transport rate for SP and CGRP in rodents has
since been found to be 11.25 mm/h, with 2030%
transported at a rate of 610 mm/h (97100). The
neuropeptides are transported in afferent nerve fibers
(Fig. 6) and stored in vesicles in the axons and in the
sensory nerve terminals (Fig. 7a).
At an ultrastructural level, co-localization of tachy-
kinins and CGRP in large dense-cored vesicles has been
documented for both the central and peripheral
projections of sensory neurons (101104), including
co-existence in nerve fibers in the dental pulp of rats
15
Fristad et al.
and cats (70, 105). In the gingiva, periodontal
ligament and pulp, sensory nerve fibers are located
both along blood vessels and as free nerve endings in
the tissue. In the pulp periphery, sensory nerve fibers
branch extensively with a dense network of nerve fibers
found in the subodontoblast layer, often penetrating
0.10.2 mm into the inner part of dentin as free nerve
endings (Figs. 7a and 8).
Fig. 6. Sensory neuropeptides, including calcitonin
gene-related peptide (CGRP), are synthesized in
neurons in the trigeminal ganglion, and transported to
oral tissues by axonal transport. Bar 5 100 mm.
Fig. 7. (A) In the pulp periphery, calcitonin gene-related (CGRP)-immunoreactive nerve fibers branch extensively with a
dense network of nerve fibers found in the subodontoblast layer, odontoblast layer and dentin. (B) Neuropeptide Y
(NPY)-immunoreactive fibers are generally found around blood vessels in the root pulp and deeper parts of pulp proper.
Bars 5 100 mm.
16
Sympathetic nerves
The sympathetic innervation of teeth derives from the
SCG (106, 107). Post-ganglionic sympathetic nerves
travel with the internal carotid nerve, join the
trigeminal nerve at the ganglion, and supply teeth
and supporting structures via the maxillary and
mandibular division of the trigeminal nerve (107,
108). Besides the classical neurotransmitter noradre-
nalin (NA), sympathetic nerve fibers contain the
neuropeptide NPY (109). NPY is synthesized in
sympathetic neurons and supplied to nerve terminals
by axonal transport (110, 111) (Figs. 7b and 9). In
contrast, NA is mainly produced locally in the nerve
terminals. Ultrastructural analysis of sympathetic nerve
terminals has demonstrated that NA and NPY are
stored in small and large vesicles, the small containing
only NA or NPY and the large containing both NA and
NPY (112). Tyrosine hydroxylase (TH) is the rate-
limiting enzyme in the production of NA and is widely
distributed in peripheral sympathetic pulpal fibers (74).
Therefore, TH has also been used for the characteriza-
tion of these nerves. The presence of adrenergic nerves
has been demonstrated in the dental pulp of various
species including man (106, 107). Sympathetic nerves
in pulp and oral tissues are sparse in number compared

Fig. 8. Sensory nerves fibers branch in the pulp
periphery, penetrating up to 0.10.2 mm into the inner
part of dentine as free nerve endings. C-fibers (green) are
located in the pulp proper, whereas A-fibers (blue)
innervate the inner part of the dentine.
Fig. 9. Section from the cervical sympathetic ganglion.
Neuropeptide Y (NPY) is synthesized in sympathetic
neurons and supplied to nerve terminals by axonal
transport (arrows). Bar 5 25 mm.
to nerve fibers conveying CGRP and SP (8, 76). The
distribution of the sympathetic fibers also differs from
the sensory nerves, as NPY- and TH-immunoreactive
fibers are normally not found in the odontoblast layer
and dentin, but are mainly associated with larger blood
vessels in the root pulp and deeper parts of the pulp
proper (8, 68, 73, 74) (Fig. 7b). An intimate structural
association between nerves and microvessels in human
dental pulp has been shown (113, 114). The vasomo-
tor nerves are mostly adrenergic in nature, and
arterioles are the most densely innervated vessels. In
addition, the distances between smooth muscle cells
Inflammatory nerve responses
and terminal axons which are crowded by synaptic
vesicles are 1520 nm in the smaller arterioles (10
15 mm in diameter).
Chemical sympathectomy, either by guanethidine or
6-hydroxydopamine, removes all TH-immunoreactive
fibers in teeth and supporting tissues. Surgical removal
of the sympathetic cervical ganglion or chemical
sympathectomy likewise eliminates almost all NPY-
immunoreactive nerve fibers in the dental pulp (68,
115, 116), indicating their sympathetic origin.
Parasympathetic nerves
The presence of cholinergic nerves in dental tissue has
been and is still controversial (117), although it has
been concluded that there is an absence of parasympa-
thetic vasodilation in the cat dental pulp (118). It has
been reported that VIP is localized in the parasympa-
thetic neurons (119, 120). The origin of these fibers is
uncertain, since no form of surgical denervation has
resulted in complete loss of VIP-containing fibers from
the peripheral target (121). VIP-immunoreactive
nerve fibers have been immunohistochemically dem-
onstrated in human (67) and feline (122, 123) dental
pulp. In rat dental pulp, however, evidence for the
presence of VIP has not been demonstrated either by
the use of immunohistochemical or by functional
methods under normal conditions; but VIP is up-
regulated in sensory neurons (124127), including the
dental pulp (127), following nerve injury (see Periph-
eral injury and neuronal plasticity).
Functions of peptidergic nerves
Sensory nerves
The tachykinins SP, NKA and neurokinin B (NKB),
and CGRP are peptide molecules released from sensory
nerve cells. Upon release, these signaling molecules
exert a broad variety of regulatory functions both in the
central nervous system (CNS) and in peripheral target
tissues (128130). The biological effects of the
tachykinins SP, NKA, and NKB are mediated by three
distinct receptors, the tachykinin receptors neurokinin-
1 (NK1), neurokinin-2 (NK2), and neurokinin-3
(NK3). Based on pharmacological features of selective
agonists and antagonists in functional studies, CGRP
acts via two main receptor subtypes, named CGRP1-
and CGRP2-receptor (131). CGRP1-receptor is
highly sensitive to the antagonist properties of
CGRP8 37 (79, 132, 133). Apart from sensory
17
Fristad et al.

Fig. 10. Immunohistochemical micrographs from the first rat molar pulp and gingiva showing CGRP-immunoreactive
nerve fibers after intermittent long-lasting tooth stimulation (A and B) and the corresponding unstimulated control (C
and D). Simultaneous recordings of systemic arterial pressure (PA) and pulpal blood flow (LDF) before, during, and after
repeated electrical tooth stimulation (arrows) of an innervated first molar (E) and 3 days after unilateral inferior alveolar
nerve axotomy (F). D, dentine; P, pulp; n, gingival; OE, oral epithelium; JE, junctional epithelium; PU, perfusion units.
Bars: (AFD) 5 100 mm. Reprinted with permission from Elsevier (134).

functions, the pulpal nerves seem to take an active part
in the maintenance of both function and structure. A
wide range of local effector functions is exerted by the
sensory nerves in peripheral target tissues. After
sensory nerve stimulation (Fig. 10), neuropeptides
are released in the tissue (134137), and mediate
sensory (138, 139) and vasoactive functions (79, 134,
140) (see also the review on circulation in this issue). In
addition, the CGRP and tachykinins are reported to
promote mitotic effects on fibroblasts (141, 142),
smooth muscle cells (143), and endothelial cells (144),
and exert influence on bone metabolism (145147)
and the micro-hardness of dentin (148). Furthermore,
CGRP stimulates bone formation in vivo (147) and
proliferation of pulpal fibroblasts in vitro (142). The
direct effects of such effector functions are dependent
on receptor-mediated signaling between nerves and
target tissues. An indirect function is also possible,
mediated by signaling molecules secreted by pulpal
cells either in a paracrine or an autocrine fashion.
Effect on the vascular system: The effects of sensory
neuropeptides on the vascular system are obtained
from tissue preparations of blood vessels from different
species in vitro. According to these results, the
mechanisms underlying smooth muscle relaxation are
either endothelium-independent or endothelium-
dependent. The endothelium-independent action
shown for CGRP (149153) seems to be mediated
through cyclic adenosine monophosphate accumulation
in smooth muscle cells. The endothelium-dependent
mechanism shown for CGRP, SP, and NKA (154, 155)
may act through the production of nitric oxide (NO; also
known as endothelium-derived relaxing factor) in
endothelial cells, which mediates second messenger
systems in smooth muscle cells. A mechanism causing
vasodilation has been proposed, acting through adeno-
sine triphosphate (ATP) sensitive K1 channels in the
vascular smooth muscle cell membrane, since K1-ATP-
activated ion channel inhibitors prevent CGRP-induced
vasodilation (156, 157). In the dental pulp, however, a
blockade of the K1-ATP-activated ion channels resulted
in a reduced resting blood flow, whereas the vasodilation
induced by tooth stimulation was unchanged (158).
Another mechanism is the indirect action on endothelial
cells via inflammatory mediators such as histamine,
bradykinin, leukotriene, and prostaglandin. The intimate

18
 Inflammatory nerve responses

Fig. 11. Pulpal survival is much better in innervated rat molars (A) at 6 days after occlusal pulp exposure, than in
denervated molars (B). That difference was not found for injuries on the side of the crown. Adapted from Bayer &
Taylor (168). Reprinted with permission from International and American Associations for Dental Research.

relationship between nerves and the vascular system is
further strengthened by the finding that blood vessels
express receptors to NGF (17).
Effect on the immune system: Reports of functional
receptors for neuropeptides on immunocompetent
cells (159163) have given further evidence that nerves
are capable of modulating the inflammatory process,
and thus take an active part in the cellular inflammatory
defense response after local injury. Intra-articular
injection of SP exacerbates arthritis in rats (164),
whereas sensory denervation with capsaicin attenuates
inflammation and nociception in arthritic rats (165),
and prevents inflammation and accumulation of
immunocompetent cells in ligature-induced perio-
dontitis (166). In the dental pulp, a less pronounced
recruitment of immunocompetent cells was found in
the tissue subjacent to deep dentinal cavities in
denervated compared to innervated teeth (167), and
pulpal damage was much greater after small pulp
exposure injury to denervated rat molars compared to
innervated teeth (168) (Fig. 11).
Following neurogenic inflammation induced by
long-term intermittent tooth stimulation in young
rat molars, accumulation of polymorphonuclear leu-
kocytes has been shown in the pulp (134) (Fig. 12),
giving further support for a role of the sensory nerves as
immunomodulators.
Transendothelial migration of immunocompetent cells
into inflamed tissues requires adhesion molecule
mediated events with activation of both selectins and
integrins (169171). Although up-regulation of adhe-
sion molecules of both integrins and members of the
selectine family has been reported after intradermal
injection of SP, CGRP, and VIP (172) in human skin,
conflicting results concerning a direct or an indirect
effect of neuropeptides on adhesion molecule activation
have been presented. It has been suggested that mast cell
degranulation after administration of SP may cause
activation of adhesion molecules in vascular endothelium
(173) and be responsible for the granulocyte infiltration
found in mouse skin (174, 175). However, the
uninjured dental pulp is almost devoid of mast cells
(176, 177), and the recruitment of granulocytes
observed during experimental neurogenic inflammation
(134) could be mediated indirectly through the release
of components from other target cells rather than via
mast cell degranulation. Macrophages are stimulated to
release cytokine by CGRP and SP (178180), and

19
Fristad et al.
Fig. 12. Immunohistochemical micrographs from the pulp proper of rat first molars. Polymorphonuclear leukocyte
(W3/13) labeled sections after intermittent long-lasting electrical tooth stimulation of an innervated (A) and
denervated (B) molar. D, dentine; n, odontoblast layer. Bars 5 100 mm. Reprinted with permission from Elsevier (134).
accumulated CGRP-like immuno-reactivity is located in
inflamed rat dental tissue (181). Neuropeptide stimula-
tion causes the release of factors such as tumor necrosis
factor and interleukin-1 (IL-1), which are important
mediators for the activation of adhesion molecules on
vascular endothelium (182186).
Earlier, the uninflamed dental pulp was believed to be
devoid of immunocompetent cells. However, studies of
uninflamed rat and human teeth (187) have shown that
a variety of immunocompetent cells are distributed in
both the coronal and apical part of the pulp. These
results have been confirmed in subsequent studies (188,
189). Macrophages are present in large numbers in
uninflamed rat dental pulp (167, 188, 189). Therefore
macrophages may be a source of inflammatory mediator
release that is important for the induction of adhesion
molecules on vascular endothelium.
As the dental pulp is submitted to continuous
stimulation from masticatory forces and frequently
exposed to antigenic components in the oral environ-
ment, a bi-directional communication between the
nerves and the immune system may be postulated. In
this way the pulpal nerves may have an important
protective function for the maintenance of homeostasis
in the pulp. In addition, the stimulating effect of
20
neuropeptides on pulpal connective tissue and en-
dothelial cells, and their vasoregulatory functions, may
be of crucial importance for tissue repair after injury to
the pulpdentin compartment.
Effect on hard tissue cells: The possibility that
odontoblasts are under nervous control, and that
nerves affect the function of odontoblasts either
directly or indirectly, has been debated. Denervation
studies have shown conflicting results concerning the
effect of innervation on dentin formation. Enhanced
secondary dentin formation was found after denerva-
tion and cavity preparation in cats (190), whereas a
reduced secondary dentin formation has been shown
after inferior alveolar nerve (IAN) axotomy and
capsaicin treatment in rats (191). At an ultrastructural
level, neonatal capsaicin treatment in rats resulted in
irregularities in dentinal tubuli, and measurements
showed a reduced micro-hardness in the predentin
(148). Recently, odontoblasts, in addition to other
pulp cells, have been shown to express receptors to
sensory neuropeptides, including SP and NKA (192,
193) (Fig. 13). Odontoblasts are derived from neural
crest cells, and both developing and mature odonto-
blasts in rats, cats, and humans express the neuro-
chemical marker protein gene product (PGP) 9.5 (8,

Fig. 13. Confocal microscopic image showing an
odontoblast labeled for neurokinin 2 (NK2) receptor
(red), which binds neurokinin A (NKA) with high
affinity. Broken line represents the border between pulp
and dentine. Reprinted with permission from Springer
Science and Business Media (192).
194, 195). PGP 9.5 belongs to the ubiquitin carboxyl-
terminal hydrolases (196), which are found to be
involved in a variety of cellular functions (197, 198).
Hydrolases have a modifying effect on receptor
function, including T-lymphocyte homing receptor
(199), platelet-derived growth factor receptor (200),
and growth hormone receptor (201). The expression
of PGP 9.5 immunoreactivity in dental epithelium
seems to be paralleled by expression of the neurotro-
phin receptor p75NGFR in rats (13, 202) and humans
(203). Thus, a function for PGP 9.5 in regulation of
cell receptors and signaling seems plausible.
The complicated neuro-immune signaling in the dental
pulp is further illustrated by the recent finding that the
odontoblasts are also possible targets for antigens, as
microbial pattern recognition receptors are shown to be
expressed by odontoblasts. In addition, odontoblasts are
able to respond to bacterial challenge by the production of
cytokines (204). The different response to Gram-negative
and Gram-positive agents raises the possibility of their
participation in innate immunity.
It is well documented that hard tissue-forming cells
in oral tissues are closely supported by sensory nerves
conveying CGRP, SP, and NKA. Functionally, there is
growing evidence for the presence of different neuro-
peptide receptors on bone cells in vitro and in vivo
(205207). The regulating mechanisms behind the
reported effects of SP on bone formation and resorp-
tion are still unclear. SP containing nerve fibers have
been localized inside resorption lacunae in cementum
and dentin following inflammatory root resorption
(208), and enhanced local SP release induces an
Inflammatory nerve responses
increased number of osteoclasts (205), indicating that
SP has a role in hard tissue remodeling. In addition, it
has been suggested that osteoblasts control osteoclast
recruitment (206). Recently, NK1 receptor has been
identified in various bone cells in the rat (192, 209).
Sympathetic nerves
Sympathetic nerves have been reported to represent
approximately 10% of the intradental nerve supply
(210). Because the majority of fibers innervating the
dental pulp are of sensory origin, the focus on nerves
and pulpal inflammation has traditionally been on
sensory nerves. However, the sympathetic nervous
system (SNS) has been shown to modulate immune
responses (211), and lately there has been a growing
interest in the role of sympathetic nerves in dental
inflammation [for a review, see (212)]. Furthermore, as
NA, the classic post-ganglionic neurotransmitter in
perivascular sympathetic nerves (213), is well known
for its vasoconstrictor role, the focus on sympathetic
nerves in pulpal hemostasis has been connected to
circulation (111, 214216).
Effect on the vascular system: The vasoregulatory
functions of sympathetic nerves in dental tissues are in
accordance with findings in other tissues. Activation of
sympathetic nerves may give rise to co-release of NPY
and NA from sympathetic nerve terminals (110, 217).
This event is followed by vasoconstriction in the dental
pulp and oral mucosa (218, 219), causing a reduction
in blood flow. The effects exerted by the sympathetic
nerves are receptor mediated, and evidence has been
provided that the dental pulp is equipped with both a-
and b-receptors (219221) and receptors for NPY
(222). The different responses on pulpal blood flow
using a1-, a2-, and b-antagonists further indicate the
presence of a1-, a2-, and b-receptors in the smooth
muscles of the pulpal vessels (223, 224). In the human
dental pulp, however, evidence for b-adrenergic
vasodilation has not been found (225). NPY exerts
vasoconstriction via a calcium-dependent mechanism
which is independent of adrenergic receptors (111,
214, 226228) and intact endothelium (229). In
addition, NPY exerts an angiogenic activity similar to
basic fibroblast growth factor, showing that sympa-
thetic nerves may be important in angiogenesis during
tissue development and repair (230).
Effect on the immune system: As both primary and
secondary lymphoid organs are innervated by sympathetic
nerves, these organs and cells of the immune system are
21
Fristad et al.
natural targets for neutrally derived NA and NPY (231).
Moreover, immunocompetent cells express adrenergic
receptors, indicating that they are controlled by the SNS
(232234). Stimulation of adrenergic receptors, either by
locally released NA or NPY, or by circulating catechola-
mines, has an effect on lymphocyte traffic, circulation, and
proliferation, and also modulates cytokine production and
the functional activity of lymphoid cells [for a review, see
(211)]. Although contradictory results have been re-
ported concerning sympathetic nerves and inflammation,
the vast majority of the reports indicate an anti-
inflammatory and inhibitory effect on immune mechan-
isms and inflammation (235237).
Activation of the SNS results in the mobilization of
blood leukocytes, a phenomenon also referred to as
adrenergic leukocytosis (238), and bilateral surgical
sympathectomy is followed by down-regulation of macro-
phage and neutrophil function, and reduced phagocytic
and chemotactic responses (239241). In the same
context, stimulation of sympathetic nerves causes recruit-
ment of CD431 polymorphonuclear cells in the dental
pulp (242) and sympathectomy impairs the recruitment of
these cells during pulpal inflammation (243).
Knockout mice, which cannot produce catechola-
mines, have normal blood leukocyte numbers and
normal T- and B-cell development and function in the
absence of infection, but exhibit reduced recruitment
of neutrophils and impaired T-cell function, including
T-helper (Th) 1 cytokine production during infection
(244). Several infectious and autoimmune diseases
have been attributed to the imbalance between pro-
inflammatory (Th1) and anti-inflammatory (Th2)
cytokines (245), and an increasing body of evidence
suggests that the SNS can alter the Th1/Th2 balance
by a shift from a pro-inflammatory (Th1) to an anti-
inflammatory (Th2) response (211). As a periapical
lesion recapitulates the pulpal inflammatory response
to bacterial infection, it provides an excellent model for
studying local immune responses. When IL-1a was
measured in rat periapical lesions, it was found that
sympathectomy increased the levels of this traditional
pro-inflammatory cytokine compared to the contra-
lateral non-sympathectomized side, again illustrating
the anti-inflammatory role of the SNS.
Effect on hard tissue cells: Histochemical approaches
have revealed that bone and adjacent tissues (bone
marrow, periosteum) have a dense supply of sensory,
sympathetic, and parasympathetic nerves (246, 247).
Quantification of neuropeptides in bone showed that
22
NPY is the most abundant (248). Osteoblasts and
osteoclasts are equipped with adrenergic and peptider-
gic receptors, which suggests neuronal regulation of
bone homeostasis (249). Studies involving either
chemical or surgical sympathectomy provide useful
information about the significance of sympathetic
nerves on hard tissue remodeling. In the majority of
studies, sympathectomy reduced osteoblastic activity
and bone apposition, whereas the number of osteo-
clasts, osteoclast surface area, and bone resorption
increased (147, 250254). Accordingly, larger peria-
pical lesions and an increased number of osteoclasts
lining the inflamed area were found in sympathecto-
mized rats when periapical lesions were induced by
pulp exposures (255). In the same study, reparative
dentin formation was reduced by sympathectomy,
showing that the effect of the SNS on odontoblasts is
similar to its effect on osteoblasts. Furthermore,
sympathectomy increases root dentin resorption dur-
ing orthodontic tooth movement (243), signifying the
inhibitory effect of sympathetic nerves on odontoclasts
in the same manner as previously shown for osteoclasts.
Cholinergic nerves
Co-localization and co-release of VIP and acetylcholine
have been reported in oro-facial tissues (41, 119, 120).
VIP is a potent vasodilator and induces vasodilation in
cat pulp when systemically infused (256). Similar to that
of CGRP, the action of VIP has been found to partially
depend on endothelium (257). The vascular effect of
VIP is reduced after administration of NO synthase
inhibitor, indicating that VIP acts indirectly via NO and
secondary messenger systems (258).
Plasticity in dental primary afferent
and sympathetic nerves
Primary sensory neurons have been extensively in-
vestigated as a model for neuronal plasticity. These
experiments have shown that the sensory neurons
undergo phenotypic changes in response to subacute
and chronic peripheral injury. Recently, adaptive
changes have also been shown for the sympathetic
nerve supply (255) (Fig. 14). This section reviews the
plasticity of sensory and sympathetic innervation of
teeth in relation to various durations and recoveries
from pulpitis, compared to irreversible pulpitis.
 Inflammatory nerve responses

Fig. 14. (A) Sections from maxillary first molar 20 days after pulp exposure, showing neuropeptide Y (NPY)-
immunoreactive fiber sprouting in the pulp adjacent to reparative dentine (RD) formation. (B) Distal root apex of
mandibular first molar. Sprouting of NPY-immunoreactive fibers is seen surrounding the larger blood vessels in apical
periodontal ligament. Bars 5 50 mm. Courtesy of Dr. S. R. Haug. Reprinted with permission from Elsevier (255).

Dental nerves and inflammation
Sensory nerves
Injuries to teeth trigger barrages of action potentials and
altered neurochemistry in all of the subregions of the
afferent neurons: dentinal and pulpal terminals, dental
and trigeminal axons, ganglion cell body and satellite
cells, central axons and a myriad of synaptic connections
in the brainstem, primarily in the nucleus caudalis. Along
with these neural changes, there are also specific reactions
of peripheral and central glia that can enhance or
modulate pain, especially if the peripheral inflammation
persists and continues to cause changes in the afferent
input to the CNS (259, 260). As indicated above in
relation to peptidergic nerve functions, there are
numerous interactions of dental sensory nerve endings
with dentin, odontoblasts, pulp cells, immune cells, and
the pulpal vascular system which induce changes within
the afferents. In turn, these affect all of the components
of pulp and the progress of inflammation, and contribute
to the tooths ability to limit initial damage, fight off
infection, and repair itself.
Tooth pulp and dentin have evolved for supporting
enamel, and a rich sensory innervation by peptidergic
and non-peptidergic nerve fibers terminates in periph-
eral coronal pulp and the inner 0.1 mm of dentinal
tubules. Sensations of sharp pain involve the faster
conducting dentinal fibers, while a diffuse ache
primarily involves specific small nociceptors and poly-
modal nociceptors, a type of sensory peptidergic fiber
that promotes tissue protection, pro- or anti-inflam-
matory action and healing after injury, as well as pain
(261, 262). There is also evidence for extensive
vasoregulation by pulpal nerve fibers (214, 263),
mechanosensitivity of fast conducting fibers (264,
265), and specific thermal sensitivity (266, 267), and
a possibility that some of the dental innervation is
participating directly in the innate immune defense by
responding to bacterial antigens (268), or by release of
neuropeptides that can mimic antimicrobial defensins
(269). When teeth become inflamed or have pulpal
damage, all of the dental neural subtypes can be
affected, and if the inflammation or trauma includes
the periodontal tissues and alveolar bone, then sensory
innervation to those tissues will also be drawn into the
cascade of neuraltissueimmune-vascular communi-
cations and reactions.
Neural reactions cause a perception of pain for most
tooth injuries, although if the damage is slow or
shallow, as during initial caries or gradual occlusal wear,
there is usually not any perceived sensation. As is true
for all tissues, the type of neural reaction, its severity,
and its duration vary depending on the extent of
damage and duration of inflammation (262). Thus,
dental neural responses to a mild injury which causes
no significant pulp damage may resolve within hours or
days, perhaps with some enhanced dentinogenesis to
form reactionary dentin (270, 271) (Fig. 15a). As

23
Fristad et al.

Fig. 15. (A) Mild injury. No pulp damage at 4 days after unetched cavity. Sprouting CGRP fibers orient under the lesion.
Reprinted with permission from Elsevier (270). (B) Reversible pulpitis. Fourth day after etched deep cavity. Abscess is
present. Calcitonin gene-related peptide (CGRP) fibers sprout outside the developing fibrous barrier. (C) Healed
reversible pulpitis with reparative dentine at 3 weeks after injury. CGRP intensity has been reduced in nearby pulp
nerves. (B and C) reprinted with permission from Elsevier (272).

dentinal cavities go deeper and approach the pulp,
there is increasing damage to the odontoblast layer,
nearby pulp, innervation, and vasculature. Those
changes cause neural reactions that persist for weeks
or months (272, 273) (Fig. 15b), and the initial injury
is more severe and more rapidly necrotic when the
sensory innervation is missing (168). If the pulp can
rebuild the pulpdentin border and seal it with
reparative dentin, then the neural reactions subside
(272) (Fig. 15c), but if irreversible pulpitis occurs, then
reacting neural endings retreat from the advancing
damage while continuing to sprout and enhance the
neuropeptide levels around the lesion (181, 274) (Figs.
11 and 16). When pulpitis becomes chronic, associated
neural changes can persist for years (275, 276). If the
peripheral changes induce persistent changes in the
CNS, then problems with referred pain, atypical facial
pain, trigeminal neuralgia and other neuropathic pain
may occur (260), as well as the long-term expression of
central regulators of gene expression such as c-Fos
(277281) (Fig. 17) and long-term glial reactions
(282). Thus, the neural contributions to pulpal
inflammation and wound healing include events at
the tooth (Figs. 15 and 16), along the nerve where
peripheral inflammation can alter conduction rates and
transganglionic conduction (283285), within the
ganglion where there can be long-term satellite cell
changes (286, 287), within the brainstem, and in the
thalamus and higher centers (288).
Sympathetic nerves
As previously described, dental neural responses to
injury vary according to the degree of damage and
duration of inflammation. The dense sensory innerva-
tion in the dental pulp has led to extensive investigation
of the involvement of sensory nerves in local inflam-
matory responses. Nevertheless, recently there is
increasing evidence for the involvement of sympathetic
nerves as well.
Not only sensory but also sympathetic nerve sprout-
ing takes place during pulpal and periapical inflamma-
tion (255) (Fig. 14). However, the timing of the nerve
sprouting varies for the different fiber types. While
sensory nerve sprouting occurs very early during pulp
injury, as early as 1 day (289, 290), sympathetic nerve
sprouting occurs around 3 weeks later (255), at which
point the sensory sprouting usually diminishes (290).

24
 Inflammatory nerve responses

Fig. 16. (A) Nerves and vital pulp are still present in roots during irreversible pulpitis when there is already a periapical
lesion with CGRP nerve fiber changes at 14 days after injury. Reprinted with permission from Alan R. Liss Inc. (274). (B
and C). Normal apex and periapical abscess at 5 weeks after a pulp exposure injury. Nerve fibers with increased CGRP
sprout around the lesion and their incoming fibers in alveolar canals are also much intensified for CGRP. Reprinted with
permission from Elsevier (181).

speculate on the involvement of NPY in throbbing

Fig. 17. Neurons in medullary dorsal horn still express c-
FOS 2 weeks after a rat molar pulp exposure injury. Adapted
from (280). Reprinted with permission from Elsevier.
A recent study in human teeth showed caries-associated
changes in the expression of NPY-immunoreactive
fibers, but any increases were limited to the tip of the
pulp horn (291). The significance of this type of
sprouting is still not clearly understood. As NPY was
shown to contribute to hyperalgesia after nerve
damage (292), it seems reasonable to assume that it
may also be involved in pain sensation during pulpal
and periapical inflammation. More specifically, one can
pain, increased sensitivity during drilling above the
pulp horns in teeth with pulpitis, and persistent
percussion sensitivity in teeth with chronic pulpal and
periapical pathosis.
Furthermore, the sympathetic nerves serve important
effector functions in relation to tissue healing. The
angiogenic effect of NPY (230) may be of particular
significance in revascularization during repair, and
reparative dentin formation is a wound healing process
in the injured pulpdentin complex. Complementary
sprouting of NPY-containing fibers was prominent
adjacent to reparative dentin after small pulp exposures
(255). Lately, the quantification of NPY levels in carious
compared to non-carious human teeth has been
performed by radioimmunoassay (293). The overall
finding that NPY levels were significantly elevated in
carious compared to non-carious teeth is in line with
previous work (291). However, within the caries group,
NPY levels were significantly elevated in mildly/
moderately carious teeth (where reparative dentin
formation is likely to be occurring) rather than in grossly
carious teeth. The finding that NPY-containing fibers
were observed in the subodontoblastic layer close to the
predentin supports the hypothesis that NPY could have
a modulatory role in reparative dentin formation.

25
Fristad et al.
In addition, a caries-associated increase has been
observed in both the number of VIP-containing fibers
(291) and the levels of VIP (294) in human pulp. As with
NPY, VIP levels were found to be higher in the pulps of
moderately carious teeth compared to grossly carious
ones (295). Moderately carious lesions may imply a
reversible inflammatory process in the pulp characterized
by vasodilation and increased pulpal blood flow. Thus,
the dynamic increase in VIP levels seen in carious teeth
may be related to the vasodilatory role of VIP. Moreover,
teeth with reversible pulpitis must have the ability to
down-regulate and eventually reverse the sequelae to
inflammation, and VIP has been identified as a potent
endogenous anti-inflammatory agent in several ways
(296). The presence of the VIP receptor, vasoactive
intestinal polypeptide/pituitary adenylate cyclise-activat-
ing polypeptide receptor (VPAC1-R), in the pulp tissue
(294) provides further support concerning the func-
tional role of VIP in pulpal health and disease.
Dental nerve injury and regeneration
Peripheral injury and neuronal plasticity
Nerve injury presents a very different survival challenge
for the neuron compared to tissue inflammation, and
the responses in terms of altered gene expression and
axonal transport show a marked contrast. When a nerve
is injured, the only way to regain normal function is to
regrow the axon, and so the neuron converts to a
growth metabolism and abandons its sophisticated
production of molecular machinery for the endings.
For example, neuropeptides such as CGRP are reduced
after nerve injury compared to up-regulation of that
peptide when the nerve endings encounter inflamma-
tion of the target tissue (297).
Following nerve injury, a dramatic shift in the
transcription of neuropeptides has been documented.
The bi-directional contact between the nerve cell and
the peripheral target tissue is lost, and the neurons
change into a state of either regeneration or neuronal
cell death. The impact on neurons in the trigeminal
ganglion is dependent on the injury site. A peripheral
injury has less impact than a more centrally located one.
However, even a small pulp exposure is shown to
induce neuronal changes both in the trigeminal gang-
lion and at the second order neuronal level in the brain
stem (277, 280) (Fig. 17). This may have implications
for hyperalgesia and chronic pain connected to
26
inflammation and nerve injury (298, 299). Even a
pulpectomy procedure implies a peripheral nerve injury
of up to 1800 unmyelinated axons in a fully developed
single-rooted human tooth (300). The number of
unmyelinated axons entering the tooth is three to four
times the number of myelinated axons (300). Thus,
pulpectomy implies deafferation of nerve fibers, which
is reported to result in an incidence of chronic pain in
25% of the cases (301303).
Peripheral injury to sensory nerves, including branches
of the trigeminal nerve in rats, is shown to induce up-
regulated neuronal transcription of NPY (59, 297, 304
307), VIP (126, 127, 308310), galanin (297, 309),
and pituitary adenylate cyclase-activating polypeptide
(PACAP) (305) (Figs. 18 and 19), whereas classical
neuropeptides are down-regulated. The altered metabolic
state is also reflected in an up-regulation of growth-
associated protein (GAP) 43 and its mRNA in sensory
neurons and in Schwann cells after peripheral nerve injury
(311314) (Fig. 20). Up-regulated GAP 43 expression is
transported peripherally and is found in axonal growth
cones and in regenerating axons (315317). Following
IAN axotomy in rats, NPY expression was located in
trigeminal ganglion cells that also exhibited an increased
expression of GAP 43 (311) (Fig. 20), indicating a role for
this protein after neuronal injury.
The functional consequences of the neuronal plasti-
city and neurochemical changes shown in injured
neurons during regeneration have so far been scarcely
elucidated. However, it has been suggested that VIP
promotes axonal regeneration and survival of neurons
after nerve injury, and is up-regulated in pulpal nerves
during regeneration (Fig. 19). In vitro studies have
shown that VIP may prevent neuronal cell death after
NGF deprivation (318) and act as a growth factor by
stimulating NPY gene expression and axonal out-
growth in rat sympathetic ganglion cells (319). In
addition, VIP is a potent vasodilator (119). Together
with the reported stimulating effect on glucogenolysis
and increase in glucose utilization (320), VIP may
serve nutritional functions important for nerve regen-
eration. A functional role for VIP after nerve injury and
during regeneration of pulpal nerves is indicated as this
neuropeptide is up-regulated in pulpal nerve fibers
under these conditions (127).
NPY has been reported to control or even inhibit
transmitter release, both at interneural synapses (321
323) and at peripheral nerve endings (324). In the dental
pulp, NPY may act in a similar manner, since activation of
 Inflammatory nerve responses

Fig. 18. Micrographs from the trigeminal ganglion (A and B) and dental pulp (C) after nerve injury. Classical
neurotransmittors such as substance P (SP) are down-regulated, whereas neuropeptide Y (NPY) is up-regulated (A and
B). The dental pulp is devoid of sensory nerve fibers after axotomy (C). Reprinted with permission from Elsevier and
Blackwell Munksgaard (59, 134, 311).

Fig. 19. After nerve injury, a pronounced up-regulation of vasoactive intestinal polypeptide (VIP) is seen in smaller-
sized neurons (arrows) in the trigeminal ganglion (left). During regeneration of sensory nerves, a coarse VIP-
immunoreactive fiber (arrows) is seen in the cuspal area approaching the odontoblast layer (right). P, pulp; D, dentine.
Bars 5 50 mm. Reprinted with permission from Elsevier (127).

27
Fristad et al.

Fig. 20. Micrographs from trigeminal ganglion (A), pulp (B), and apical periodontium (C) 4 days after nerve injury
(axotomy). Growth-associated protein (GAP) 43 is up-regulated in trigeminal ganglion neurons (A). In pulp (B) and apical
periodontium (C), thick coarse nerve profiles are GAP 43 immunoreactive. D, dentine; PDL, periodontal ligament; AB,
alveolar bone. Courtesy of Dr. S. M. Khullar. Reprinted with permission from Blackwell Munksgaard (311).

sympathetic nerves in rat incisors has been shown to
counteract vasodilation and plasma extravasation induced
by the sensory nerves (325). Neurons in the trigeminal
and dorsal root ganglion of rats, rabbits, and monkeys are
found to express receptors for NPY (326). Therefore,
NPY may regulate transmitter release during nerve
regeneration, thus inhibiting nociceptive input centrally
and influencing vasoregulation in peripheral targets.
NPY has been found to accumulate in peripheral
neuroma after tight ligation or transection of the rat
sciatic nerve (327) and thus transport of NPY in sensory
nerves has been suggested. Further evidence for the
transport of NPY in primary afferent nerves during IAN
regeneration in oro-facial tissues has been shown by the
increased expression of NPY in the trigeminal ganglion
(Fig. 18), the IAN, and in the teeth and supporting
tissues of rats (59, 328, 329). Double immunolabeling
has shown the co-existence of CGRP and NPY in both
trigeminal neurons and pulpal nerves during regenera-
tion after IAN axotomy (59) (Fig. 21).
The functional role of the neuronal transcription of
galanin and PACAP after injury is still not completely
understood. However, PACAP has been reported to
induce a long-lasting suppression of a C-fiber evoked
flexor reflex in rats (330), and galanin seems to inhibit
the release of classical transmitters at least in the CNS
(331). Functional recovery is rarely complete for
trigeminal nerves, though many axons find their way
back to the tooth with guidance from growth factors
such as NGF (332).
Dental nerve injury and regeneration
Dental nerves can be injured in two ways, either by
direct injury to specific trigeminal nerve bundles that
are en route to the teeth (nerve avulsion during tooth
extractions, jaw trauma, etc.), or by the regression of
tooth nerve endings away from advancing pulpal
necrosis until the main nerve becomes involved in the
root, periapex, and alveolar canal (Fig. 16). When an
alveolar nerve in rats is transected or crushed, the cut
axons find their regeneration path quickly and can
return to the denervated pulp and dentin of rat molars
in only 23 weeks in order to rebuild their initial
dentinal terminal in synchrony with the return of the
jaw opening reflex response to electric tooth stimula-
tion (333, 334). In that situation, the original pulp
dentin complex will not have been damaged and

28

Fig. 21. Double immunofluorescence labeling showing
co-localization of NPY and CGRP in pulpal nerve fibers
(arrows) during regeneration of sensory nerve fibers.
Sections show the subodontoblast and odontoblast layer
(OB) of a first mandibular rat molar. Reprinted with
permission from Elsevier (59).
Fig. 22. (A) At 90 days after replantation of rat first molars, some of the pulps retain columnar odontoblasts (Od) and
associated innervation beneath reactionary dentine (small arrows), while other regions have reparative dentine (Rd) (B).
Nerve fibers (arrowheads) are sparse in the repaired dentine. Bars 5 100 mm. Reprinted with permission from John Wiley
and Sons Inc. (335).
Inflammatory nerve responses
appears to be directing some aspects of the regeneration
through the release of growth factors from the
odontoblasts and/or nearby cells, since those growth
factors have the same density of expression as the
sensory innervation terminal patterns (335). Detailed
analysis of the electrophysiology of reinnervated teeth in
cats and ferrets has shown that there is excellent return
of sensory fibers but that they mostly have slower
conduction rates than under normal conditions (336).
The responses in a physically denervated tooth have
been reported to include increased dentinogenesis as if
the normal sensory innervation holds odontoblasts and/
or their associated vasculature in a retarded dentinogen-
esis state (190). With chemical denervation subsequent
to post-natal capsaicin exposure, there is dysplasia of the
dentinal tubules and the dentin matrix is softer than it
should be (148). The tooth replantation model is an
interesting denervation/regeneration model in which
young rat first molars are extracted and then immediately
replaced in the sockets, thereby denervating and
devascularizing the tooth (337). In that situation, the
sensory fibers and blood vessels begin to re-enter the
pulp within days, and can rebuild a normal innervation if
the original odontoblasts and pulpdentin complex
survived the trauma (335) (Fig. 22), but more
commonly encounter reparative dentin or bone depend-
ing on the pulpal reaction to extraction/replantation.
29
Fristad et al.

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