Nerve Degeneration

Although much is known concerning the response of pulpal axons to physical and bacterial
insults, other important questions remain. One of the least understood is the relationship of axon
degeneration to pulpal pain states. Degeneration of pulpal axons in response to injury is a
common finding when painful pulp tissues are evaluated (see Fig 7-11f). Although degenerating
axons are observed in areas of pulpal necrosis, they are also commonly found to be intermixed
with intact fibers within painful specimens.
The factors that influence the progression of the degenerating response are unknown but
may relate to neuroimmune interactions that are prevalent in the inflamed dental pulp. The
presence of degenerated fibers intermixed with intact ones also suggests a differential response
to injury among various fiber types, with important implications for pain mechanisms. Although
degeneration of axons may influence pain mechanisms, a more likely process involves the
remodeling of axons that occurs before or in the absence of degeneration. This change in
structure in response to inflammatory influences most likely involves a remodeling of ion
channels and receptors that could affect the sensitivity and activity of nociceptors.
This response is further complicated by the gradient of inflammatory changes that exist
within the diseased dental pulp123 and the effect of this inflammatory gradient on different
regions of the same axon, with important implications for the development of intense
spontaneous pain that may accompany the pain of toothache. These changes at individual sites
suggest that pulpal pain mechanisms may relate not only to broad global changes but also to the
effect of the lesion on isolated fibers. The painful human dental pulp presents a model system in
which future studies can relate changes at localized sites to pain states.

Neurophysiology of Pulpal Nociceptors and Dentinal Sensitivity

Distinct groups of pulpal afferent nerve fibers can be classified, as described earlier. The
classification is based on both the morphology and conduction velocities of the afferents. A
number of recent studies indicate that these neuronal classes are functionally different and that
their activation may mediate different types of prepain and pain sensations.124 Generally, these
studies indicate that firing of pulpal afferents in human teeth induces mostly, if not entirely,
painful sensations125,126 and that temporal summation (increase of the electrical stimulation
frequency) of low-intensity electrical stimulation changes the nonpainful (prepain) sensation to a
painful one.127 However, the type of pain may vary according to the type of stimulus applied,
the type of fibers activated, or the condition of the pulp. Most studies suggest that
mechanosensitivity5 or thermosensitivity128,129 of pulpal nerve fibers does not induce
mechanical or thermal perceptions in people,1 although there is recent evidence for intradental
vibration detection by humans130 and dental Aβ-dependent brain activity.131
Tissue injury and inflammation can sensitize and activate pulpal afferents. In previous
experimental studies on animals, pulpal inflammation has been associated with reduced
thresholds to external stimulation and spontaneous discharges of pulpal nerve fibers.124,132,133
These changes are probably due to synthesis or release of a number of different mediators, which
have been shown to activate pulpal nerves and sensitize them to external stimuli24,132–134 (see
chapter 8).
Application of a cold stimulus to hypersensitive dentin in human subjects induces pain
that, in many cases, can reach a very high intensity.133,135 Moreover, patients experiencing
acute pulpitis often report moderate to severe pain.136 However, this is not invariable: Pulpitis
may proceed to a total pulpal necrosis with only minor symptoms or without any symptoms at
all.24,136 Considering the exceptionally rich nociceptive innervation of the pulp, such
asymptomatic cases (“silent pulpitis”) are puzzling. However, recent studies indicate that pulpal
nociceptor activation may be abolished by local inhibitory mediators (eg, local opioids,
cannabinoids, or somatostatin)14,24,137 or by loss of functional terminals of these fibers (eg, via
apoptosis or secondary to liquefaction necrosis). In addition to these peripheral factors, other
central neural mechanisms may have a significant impact in the development of dental pain
conditions14,24,65,138,139 (see chapter 8).
Collectively, these studies indicate that there is a poor correlation between clinical pain
symptoms and the histopathologic status of the pulp.136,140 This is not surprising considering
that hyperalgesia is a perceptual event mediated by peripheral and central pain mechanisms at the
molecular level; these mechanisms are not necessarily discernible with microscopes evaluating
biopsies of human dental pulp. In the following sections, the function of the pulpal neurons in
healthy teeth and their responses to tissue injury and inflammation are described. The role of
different pulpal nerve fiber groups in the mediation of pulpal and dentinal pain under normal and
pathologic conditions are discussed in the next two chapters (see chapters 8 and 9).

Sensory functions of pulpal nerves under normal conditions

A major part of current knowledge regarding the function of dental nerves is based on
electrophysiologic recordings performed on animals (eg, cats, dogs, and monkeys). In such
experiments, single intradental nerve fibers are identified and their responses to various stimuli
recorded (Figs 7-15 and 7-16). These electrophysiologic responses to various external stimuli
have been compared to the perceptual responses induced by the same stimuli applied to human
teeth. Such comparisons have shed light on how different pulpal nerve fiber groups contribute to
different pain responses under normal and pathologic conditions. The morphologic similarity of
the intradental innervation of animals and humans serves as a good basis for such comparisons.
The classification of the pulpal primary afferents as A and C fibers is based on their
conduction velocities measured in single–nerve fiber recording experiments142–145 (see Figs 7-
15 and 7-16). These two classes correspond to the myelinated and unmyelinated fibers found in
morphologic studies.3,38,146 According to the results of electrophysiologic recordings, the A
and C fibers are functionally different. 1,13,37,127,128,133,147 In addition, the A-fiber group is
not uniform because some slow-conducting (small) A fibers seem to be sensitive to capsaicin,
whereas most of the faster-conducting fibers respond to hydrodynamic stimulation but are not
activated by capsaicin.13,37,133
The results of electrophysiologic studies also indicate that C fibers do not respond to
dentinal hydrodynamic stimulation. Instead, the sensitivity of dentin is entirely based on the
function of intradental A fibers.135,141,145 Comparison of the sensory responses from
stimulated human teeth to the electrophysiologic responses from animal studies reveals
functional differences between these two fiber groups in response to tissue
injury.1,13,124,133,145,148
As already mentioned, pain and prepain are the only sensations that can be evoked by
intradental nerve stimulation in human subjects, although there is recent evidence for intradental
vibration perception. 130 The quality of the pain can vary depending on the type of stimuli
applied and can range from sharp, stabbing pain to dull, aching, throbbing pain
sensations.1,125,134,143,148,149 The variation is caused by activation of different nerve fiber
types and differences in the nerve firing patterns (temporal summation) evoked by various
stimuli.127,128,135,149
 The application of low-intensity electric stimulation of human teeth can produce a
nonpainful sensation. 125–127 It has been proposed that intradental low-threshold and fast-
conducting Aβ-type afferents mediate such prepain sensations.125,127 Aβ fibers do have low
electric thresholds; however, the thresholds of Aβ and Aδ fibers overlap considerably (Fig 7-17),
and, accordingly, both fiber groups may be involved in the mediation of prepain sensations.124
It is also important to note that painful sensations can be induced by increasing the stimulation
frequency at prepain intensities,127 a procedure that produces temporal summation of the nerve
activity at the level of the trigeminal nuclei. Collectively, these findings suggest that prepain and
pain sensations are mediated by the same afferent fibers.
On the basis of the single-fiber recordings (see Fig 7-17), it can also be concluded that
activation of only a small number of pulpal afferents is needed to evoke prepain or pain
sensations.124 This is clinically important because it suggests that pulp testing may produce a
false-positive response, even in teeth with extensive pulpal necrosis, as long as at least some
pulpal axons are still responsive. This could explain Fig 7-15 Setup for electrophysiologic
recording of single intradental nerve fibers. The inferior alveolar nerve is exposed, and the nerve
filaments are dissected from the nerve trunk. Single fibers innervating the canine or incisor teeth
are recorded using metal wire electrodes (R). The nerve fibers are identified using electrical
stimulation applied to the tooth crown. (Reprinted from Närhi and Hirvonen141 with
permission.)
Fig 7-16 Nerve recording from a nerve filament containing one A and one C fiber. The action
potential of the A fiber shows after a latency of only about 2 milliseconds (ms) after the
electrical stimulus artifact on the left (arrow). The C-fiber action potential on the right is delayed
by about 30 ms because of slow conduction along the axon. The conduction velocity of the
recorded fiber can be calculated by dividing the conduction distance (the length of the nerve
fiber) by the conduction delay.

Fig 7-17 Electrical thresholds of intradental nerve fibers of the cat canine tooth plotted against
their conduction velocities. Responses for C, Aδ, and Aβ fibers are shown. The Aβ and fast Aδ
groups both have very low thresholds compared to the slower Aδ fibers and C-fiber groups.
(Modified from Närhi et al124 with permission.) the clinical observation of a positive pulpal
response in a tooth with a periradicular radiolucency (see also chapter 17).
It has been suggested that non-noxious mechanical (tactile) stimulation of or pressure
applied to the intact tooth crown activates pulpal Aβ fibers.5,131,150 On the basis of such
findings, those fibers were regarded as a discrete functional group that would be involved with
the regulation of masticatory functions, the sensation of food texture between the teeth, and the
control of occlusal forces. However, Aβ and Aδ fibers show similar responses to various external
stimuli and to inflammatory mediators, 124,133,142–145 and the results suggest that the fibers
may belong to the same functional group.
Taken together, the results of human and animal experiments indicate that a
hydrodynamic mechanism mediates intradental nerve activation in response to several different
stimuli1,2,136,147,151–154 (see chapters 8 and 9) as well as release of neuropeptides. 134,155
The responding fibers consist of the Aδ and Aβ classes of neurons (Fig 7-18). Considering the
tissue distortion and injury in the dentin-pulp border related to their activation,152 the
responding receptors can be classified as high-threshold mechanoreceptors or mechanical
nociceptors.
 The pulpal C fibers are polymodal because they respond to several different modes of
stimulation and have high thresholds for activation.124,128 They are activated only if stimuli
reach their terminal endings inside the pulp. In an intact tooth, given the insulating enamel and
dentinal layers, rather intense thermal stimuli are needed for their activation. The insensitivity of
pulpal C fibers to dentinal (hydrodynamic) stimulation124,142 is consistent with the location of
their endings and receptive fields deep in the pulp.3,11,142–145
Pulpal C fibers also respond to histamine and bradykinin applied to the exposed
pulp13,124 (Fig 7-19), which indicates that this fiber group also may be activated in connection
with pulpal inflammatory reactions. Thus, the dull pain induced by pulpitis may be evoked by C-
fiber activation. C fibers also respond to capsaicin, which is a selective irritant of small
nociceptive- and neuropeptide-containing afferents.124,156
Fig 7-18 Responses of a single intradental A fiber to probing (a); an air blast (b); application of
hypertonic, 4.9-mol/L calcium chloride to dentin (c); and drilling of dentin (d) over a period of
1.5 seconds. The approximate timing of the stimulus application is indicated by the horizontal
lines in (a), (b), and (d) and by the arrow in (c). (Reprinted from Närhi et al145 with permission.)
Fig 7-19 Responses of a single intradental C fiber (small action potential) in the exposed pulp of
a cat canine tooth to bradykinin application (BK) and after washing with physiologic saline
(NaCl). The A fiber (large action potential) in the same nerve filament only shows firing of a
single action potential at the time of the bradykinin application, probably because of a
mechanical effect. (Reprinted from Närhi13 with permission.)
Fig 7-20 Responses of intradental nerve fibers to intense heating of an intact cat canine tooth.
The timing of the stimulus application is indicated by the horizontal line. The A fiber (large
action potential) in the filament gives an immediate response at the beginning of stimulation. In
contrast, activation of the C fiber (small action potential) is much delayed. (Reprinted from
Närhi13 with permission.)
The application of intense heating or cooling to human teeth produces a sharp pain
sensation with a short latency, typically within a few seconds. If the stimulation is continued, a
dull, radiating pain response follows.1,128 Correspondingly, biphasic responses to thermal
stimuli are observed in cat teeth (Fig 7-20). The first response is an immediate or short-latency
firing of intradental A fibers, followed by a delayed C-fiber activation.124,142–145 The initial
A-fiber responses are supposedly induced by the dentinal fluid flow resulting from the rapid
temperature changes.136,148,157 The delayed C-fiber activation is probably induced by a direct
effect of heat and cold on the nerve endings in the pulp.124,128,142
The results of these thermal-stimulation studies strongly indicate that intradental A and C
fibers may mediate different perceptual qualities of dental pain, ie, sharp and dull, respectively.
In addition, certain other stimuli, such as air drying of exposed dentin and application of
bradykinin to the exposed pulp, which are known to activate pulpal A or C fibers selectively, are
also able to induce either sharp or dull pain, respectively, in human experiments.125,157
Fig 7-21 Activation mechanisms of intradental nerve fibers. A fibers in the dentin-pulp border
area respond to stimulusinduced fluid flow in the dentinal tubules and consequent deformation of
the peripheral pulp tissues containing the nerve endings (hydrodynamic mechanism). For C-fiber
activation, the applied stimuli must reach the nerve endings, which are mostly located deeper in
the pulp. C fibers also respond to certain inflammatory mediators.