Pain Pathways and Mechanisms of the Pulpodentin Complex

Anibal Diogenes, DDS, MS, PhD

Michael A. Henry, DDS, PhD

Pain conditions are common in areas innervated by the trigeminal nerve, and this especially includes
odontalgia (toothaches).1,2 It is estimated that approximately 12% of the US population suffers from
odontalgia, being the primary reason patients seek oral health providers.3,4

Although the subject of pain is of considerable importance to all health care providers, the simple
reality is that many patients consider pain and den-tistry to be synonymous. This association often leads
to fear and anxiety, causing patients to delay treat-ment, ignore their initial symptoms, and contact oral
care providers only when the pain is unbear-able (high intensity and chronic). 5 This association is largely
based on the patient’s preexisting pain and previous untoward experiences following stimula-tion of
dental nociceptors during treatment. Other factors, such as ethnicity, age, and gender, have all been
correlated with different reported pain levels.6,7 In addition, the media sometimes portray dentists and
oral care providers negatively as professionals indifferent to their patients’ pain, reinforcing anxiety
toward dental treatment.8

In dental pain, activation of pulpal nociceptors is the initial step that ultimately results in the pain
experience. However, pain is much more than acti-vation of peripheral nociceptors; instead, pain rep-
resents an integration of nociceptive signals and emotional, cognitive, and affective components that
make pain such a terrible experience. 9 Clinicians and researchers must never forget to appreciate this
aspect of the pain experience.

Diagnosis and management of pain represent foundation skills necessary for the successful practice of
dentistry and are especially critical when the patient with odontalgia is evaluated. 10 Accordingly, this
textbook provides an extensive review of pain mechanisms that are critical to the evaluation of the
patient with odontalgia, including pulpal inflammation (see chapters 4, 10, and 11), neuroanatomy, and
neurophysiology of the dental pulp (see chapter 7), as well as effective pharmacologic and
nonpharmacologic strategies for managing dental pain (see chapter 9). The present chapter specifically
contributes to the development of this foundation skill by reviewing peripheral and central nervous
system mechanisms associated with the pain response following stimulation of the pulpodentin complex.
This knowledge base should help clinicians to make more accurate diagnoses and to design more
effective pain-control strategies for their patients.

The awareness of pain involves three steps: (1) detection, (2) processing, and (3) perception (Fig 8-1).
Detection is a function of the peripheral sensory (afferent) neuron; processing involves the selective
activation of specific and related central nervous system pathways that is largely dependent on initial
processing done within the medullary and spinal dorsal horns; and perception is the result of activ-ity in
more rostral brain regions such as the cerebral cortex. Together, the activities of these structures are
responsible for the complex multidimensional aspect of pain that includes pain both as a sensation and as
an emotion.11 The clinician that diagnoses and treats odontalgia should consider the contributions pro-
vided by each of these steps because the pain experi-ence is ultimately shaped by activity of these
various structures. The neuronal activity within these different pathways can change depending on the
absence or presence of disease; because most patients who seek endodontic therapy have disease, these
modifying processes are active at the time of the clinical evaluation and may add to the challenges
associated with the diagnostic task. This chapter reviews those peripheral and central pain mechanisms
that should be considered when the clinician evaluates the symptomatic patient.
Fig 8-1 General steps in pain transmission in the orofacial region. Detection of noxious injury occurs
via primary afferent nociceptors that travel in one of the three divisions (div) of the trigeminal nerve
(ophthalmic, maxillary, and mandibular). (In certain chronic pain conditions, detection also may
occur by other afferent fibers such as the Aβ fibers.) Processing occurs primarily in the medullary
dorsal horn. Nociceptive signaling may be increased by central mechanisms of hyperalgesia or
allodynia. Nociceptive signaling may also be reduced by endogenous analgesic systems. The output
from the medullary dorsal horn is conveyed predominantly along the trigem-inothalamic tract.
Perception occurs primarily in the cerebral cortex. Other sensory nerves are also responsible for
additional craniofacial signaling (eg, cranial nerves [CN] VII, IX, and X as well as afferent fibers
from the cervical spinal cord).
 Pathways Responsible for Detection, Processing, and Perception of Dental Pain

Odontogenic pain is usually the result of a noxious physical stimulus or the release of inflammatory
mediators that stimulate receptors located on the terminal endings of nociceptive (pain-detecting)
afferent C and Aδ nerve fibers12–16 (see chapter 7). Physical stimuli, via their effect on dentinal fluid
flow, can activate the nociceptors that innervate dentinal tubules, leading to the perception of dentinal
pain16 (Fig 8-2). Inflammatory mediators, via activation of their respective receptors, can sensitize or
depolarize the nociceptors that innervate pulp tissue. These topics are discussed in detail later in the
chapter and elsewhere.17 Experimental studies have shown that activation of nerves within the dental
pulp by these physiologic (eg, thermal, mechanical, or chemical) stimuli results in a pure sensation of
pain, although other studies using certain electrical stimuli can elicit a “prepain” sensation.18

The activation of the peripheral nociceptor produces a generator potential; if great enough, this
depolarization will trigger a nerve impulse (action potential). The action potential is propagated along
a peripheral trigeminal nerve to the primary afferent neuronal cell body located in the trigeminal
ganglion and then into the central nervous system along the central process of this same neuron 14,19–21
(Fig 8-3).

The central process of the primary afferent cell body enters the brainstem at the level of the pons
by way of the trigeminal root entry zone and then enters the trigeminal tract. The trigeminal tract
carries the primary afferent fiber to the trigeminal sensory nucleus located in the pons and medulla,
where it then terminates. The most rostral portion of the trigeminal sensory nucleus is the main
sensory nucleus, while the caudal portion is represented by the spinal trigeminal nucleus. The spinal
trigeminal nucleus is further subdivided into the following subnuclei: pars oralis (most rostral), pars
interpolaris, and pars caudalis (most caudal).22,23
Fig 8-2 Two mechanisms for the periph-eral stimulation of nociceptive nerve fibers in tooth pulp.
Acute dentinal pain: According to the hydrodynamic theory, stimuli that cause fluid movement in
exposed dentinal tubules result in the stimulation of noci-ceptive nerve fibers. Pain with inflamma-
tion: Inflammation is associated with the synthesis or release of mediators, including prostaglandins,
bradykinin, substance P, and histamine (as well as other mediators not shown). The interrelationships
of these inflammatory mediators form a positive feedback loop, allowing inflammation to persist far
beyond cessation of the den-tal procedure. Pi, intrapulpal pressure; NGI, neurogenic inflammation;
CGRP, calcitonin gene–related peptide; NGF, nerve growth factor; GDNF, glial cell line–derived
neu-rotrophic factor; NPY, neuropeptide Y; NE, norepinephrine.
Fig 8-3 Pathway and confocal micro-graphs of neuroanatomical structures responsible for the
transmission of pulpal nociceptive stimuli within the trigeminal system. Peripheral nociceptive nerve
fibers terminate as free nerve endings within the dental pulp (a) and arise from primary afferent cell
bodies within the trigeminal ganglion (b). The central processes of these primary afferent cell bodies
pass into the brainstem and enter the trigeminal tract. These fibers exit the tract to terminate within the
trigeminal sensory nucleus (c), composed of the main sensory nucleus (MSN) and the spinal
trigeminal nucleus. The trigeminal nucleus consists of pars ora-lis (PO), pars interpolaris (PI), and
pars cau-dalis (PC). (a) Pulpal nerve fibers are seen within the pulp horn of a human specimen and are
stained with antibodies against N52 (green), PGP9.5 (blue), and TRPA1 (red). A nerve fiber bundle
(arrowhead) gives rise to an extensive arbor within the subodontoblastic plexus and with some fibers
that enter and traverse (arrow) the odontoblastic layer (O). (b) Neuronal cell bodies are seen within
the rat trigeminal ganglion and are stained with antibodies against peripherin (green; black arrow),
TRPV1 (blue; arrowhead) and CGRP (red; white arrow). Larger cell bodies lack staining, while the
smaller cell bodies are stained individually or multiply with these antibodies used to identify
nociceptors. (c) Intrinsic neuronal cell bodies are stained with NeuN (green; arrow), and the central
pro-cesses of CGRP-containing primary afferent fibers (red) are seen within a transverse section of
the rat brainstem at the level of caudalis. The CGRP-containing primary afferent fibers are located in
the trigeminal tract (T). Some of these fibers exit the tract (arrowhead) to enter and terminate
especially within the superficial laminae I and II outer (o) zones of caudalis, where they form
synapses with processes of intrinsic and descending neurons.
 Animal studies have shown that primary afferent neurons that innervate dental pulp terminate in
all of the different subnuclei located within the ipsilat-eral trigeminal sensory nucleus, including
prominent projections to caudalis.24 The projection to cau dalis is expected because the tooth pulp is
rich in pain fibers, and trigeminal primary afferent input to caudalis has been linked to facial pain:
Trigeminal tractotomy at the level of pars caudalis in humans results in the loss of pain and
temperature sensation over facial structures while preserving touch sensa-tions, 25 thus demonstrating
a critical role for caudalis in facial pain perception. Even so, additional stud-ies have shown that
neurons located in more rostral nuclei can be activated by intraoral and perioral nociceptive stimuli,
even after trigeminal tractotomy at lower levels, and together these studies demon-strate a broad
projection of tooth pulp nociceptors throughout the trigeminal sensory nucleus. 26 These projections
form an important structural founda-tion for referred pain mechanisms that are of critical importance
when the symptomatic patient is evaluated.
Fig 8-4 Functional processing of nociceptive input in the nucleus caudalis of the medullary dorsalhorn
(MDH). In this example, activation of pulpal C nociceptive fibers leads to the release of glutamate
(Glu) and substance P (SP), which are conveyed acrossa synapse to a wide dynamic range (WDR)
projection neuron. This projection neuron projects to the thalamus; the information is then relayed to
the cortex. Glutamate binds and activates either N-methyl-D-aspartate (NMDA) or α-amino-3-
hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors, while substance Pbinds and activates
the neurokinin 1 (NK1) receptors. The sensory fibers can directly activate the WDR neuron or
indirectly activate it via contacts with excitatory interneurons. Several signal transduction pathways
have been implicated in modulating the responsiveness of projection neurons, including the protein
kinase A (PKA) and protein kinase C (PKC) pathways. Projection neurons can themselves modulate
nearby cells by synthesis and release of prostaglandins (PGs) via cyclo-oxygenase (COX) and nitric
oxide (NO) via nitric oxide synthase (NOS). Glia can modulate nociceptive processing by release of
cytokines (interleukin 1β and tumor necrosis factor) and prostaglandins. Descend-ing terminals of
fibers originating in regions such as the nucleus raphe magnus (NRM) or locus coeruleus (LC) can
release serotonin (5HT) or norepinephrine (NE). Also depicted are the major proposed receptors for
these neurotransmitters. Drugs that alter these receptors or neurotransmitters have potential as
analgesics. 5HT1A/D, 5HT receptor; GABA, γ-aminobutyric acid; GABA B, GABA receptor; PAG,
periaqueductal gray; NC, nucleus caudalis; TGG, trigeminal ganglion; M-ENK, met-enkephalin; δ/μ,
δμ-opioid receptor; α2, α2-adrenergic receptor.