 Nerve Supply of the Pulpodentin Complex and Responses to Injury - Overview

 Innervation
o One of the most densely innervated tissues in the body
o Rarely perceive sensation unless injured or inflamed
o Seems to only sense pain- nociception
 Physiology
o Sensory fibers
 Important interactions with other pulpal cells contribute to pulpal health
o 1).Odontoblasts
o 2).Fibroblasts
o 3).Blood vessels
o 4).Immunocompetent cells
 Profuse innervation of pulp and dentin containsneuropeptide rich secreting fibers
 Timing, concentration and location of secretions act as important signals for
pulpal cells for status of tooth.
 Neural agents important agents signaling for
o neurogenic inflammation
o repair
o for everyday “housekeeping functions” near pulp-dentin border

o Pulpal fibroblasts make neurotrophin growth factors (NGF)

 Expression of factors change after injury
 Changes detected by high affinity receptors on:
 Odontoblasts
 Immune cells
 Nerve fibers:
o Trk A receptor has affinity for NGF, 12 hrs after injury, mRNA
expression was increased by 73% and remained high in ganglian for
14 dyas. NGF can mediate repair and pain.
o Sullins JS, Carnes DL, Kaldestad RN, Wheeler EF. Time course
of the increase in trk A expression in trigeminal neurons after
tooth injury. J Endodon 2000;26:88-91
 Cells adjust their responses:
 Enhancing defense in tissue repair phenotypes
 Begin returning to normal resting condition, depending on homeostatic
needs of pulp
o Cells in pulp respond directly to
 Endocrine
 Paracrine
 Autocrine signals
o Nerve cells have cell body located in trigeminal ganglion for sensory fibers, cervical
sympathetic ganglia for sympathetic fibers
 a.Retrograde axonal transport required to transport tissue factors to cell body

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  b.New neuropeptides, receptors, or ion channels sent back to the endings via
anterograde transport
 c.Sequential axonal transport signals alter neuronal gene expression and
phenotype
 d.Round trip takes hours to days
 e.Electrophysiological signals trigger pain and defensive reflexes via action
potential signaling
 1).Action potentials travel along nerve membranes
 very rapid
 2).Chemical signals carried by axonal transport
 much slower
 f.Additional interactions with pulp involve
 1).Endocrine
 2).Paracrine
 3).Autocrine signals responses in nerve endings
 4).Efferent action potentials backfire sensory nerve ending
releasing neuropeptides

 B.Normal Anatomy of Dental Innervation

o 1.Types of innervation and terminal locations
 a.Sensory innervation of teeth terminates primarily in coronal odontoblast layer,
predentin, and inner dentin.
 b.Each sensory neuron has cell body in trigeminal ganglion, numerous central
synaptic endings, and a long peripheral axon that travels in a nerve to target tissue,
where axon makes receptive endings.
 c.Sympathetic neurons originate in sympathetic ganglion and end near dental blood
vessels and central pulpal cells
 d.At central endings are synaptic connections with local circuit neurons and
projection neurons as well as descending modulation from the brain
 Six different kinds of nerve fiber each with preferred location
 1). A-beta (small proportion)
o a).medium-sized
o b).myelinated fibers
o c).Innervate mainly dentin and dentin-pulp border near pulp horn tip
o d).Lack low-affinity NGF receptors
o e).Most sensitive fibers to mechanical (hydrodynamic) stimulation
o f).Form some large endings making close appositions with
odontoblasts (Gunji fibers?)
 2).A-delta, fast (25 – 50% of dental nerve fibers)
o a).Small
o b).Myelinated
o c).Contain neuropeptide CGRP
o d).Express receptors for NGF
o e).Most innervate dentin, predentin and odontoblast layer underlying
enamel

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 o f).Those ending close to odontoblast processes my form some type
of association with them
 i).No gap junctions have been found for nerve-
odontoblast associations – BYERS!!!
 ii).Paracrine signaling mechanism would be
facilitated by closeness
o g).Innervation is concentrated in dentin near pulp horn tip
o h).Least frequent in root dentin
 3).A-delta slow polymodal fibers (Few)
o a).Slow-conducting thin
o i).Have capsaicin sensitivity
 4).C-fibers Nociceptive (majority of dental nerve fibers)
o a).Unmyelinated
o b).Slowly conducting
o c).Regulated by:
 i).NGF in adult
 ii).Half require NGF during development
 iii).Others utilize brain-derived neurotrophic factor
(BDNF) or
 5).C-fibers, glial-derived neurotrophic factor (GDNF) regulated
 6).C- fibers Polymodal
o i).Responsive to capsaicin
o ii).Responsive to inflammatory mediators
 a).Histamine
 b).Bradykinin
o e).Express NGF-receptors and neuropeptides
 i).Substance P
 ii).CGRP
 iii).Neurokinin A
o f).terminate in peripheral pulp or along blood vessels
o g).Mostly activated by pulpal damage
o h).Some respond to intense heat or cold
o f.Axon caliber of nerves entering teeth from C to A-beta sizes branching and becoming
progressively narrower in cervical and crown levels until all are unmyelinated in the cell-
rich, cell-free, odontoblast and dentinal regions
o g.These nerve fibers are dynamic and continually adjusting their association with pulpal
cells and dentin
 1).Growth-associated protein-43 in dental nerve fibers and endings
o h.Other cytochemical features of dental nerve fiber subgroups have been identified
 1).Calcium-binding proteins or receptors for nociceptor modulating agents
 a). opioid peptides
 b). somatostatin
 c). cannabinoids
 d). excitatory amino acids

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  e). ATP
o i. Of interest in dental innervation: some intradental
fibers are branches from larger, faster-conducting
“parent” axons located outside
o j. Key feature of all above: all have specific membrane
receptors for chemical signaling with neighboring cells
 1). NGF is made by pulpal fibroblasts for signaling to:
o a). odontoblasts
o b). dendritic cells
o c). nerve fibers
o other fibroblasts
 2). Some neural responses to NGF involve axonal retrograde transport back to
the trigeminal ganglion for induction of altered gene expression.

 Sympathetic and parasympathetic innervation of teeth

o 1.Vasodilatory functions of sensory innervation are opposed by vasoconstriction by
sympathetic fibers
 Sympathetic fibers much less numerous than sensory
 Sympathetic fiber distribution differs from sensory fibers
 Deeper pulp
o Tissue concentrations are 11x greater than those in the gingiva.
Surgical sympthectomy reduced the NA content in pulp by 76% in
rat incisors
 Kerezoudis
 Along blood vessels
o There are sympthatetic nerve fibers in pulp that are activated by
electrical stimulation of teeth, resulting in alpha and beta
adrenoceptor-mediated blood flow responses
 Kerezoudis
 Parasympathetic activity is much less than sympathetic
 Developing and primary teeth
o Innervation enters pulp during crown stage
 Makes branches near pulp horn odontoblasts
 Rapid increase in nerve fiber entry into dentin upon eruption
 Innervation density continues to increase during maturation
 Areas with tertiary dentin or dead tracts or reparative regions lose most dentinal
innervation
 Sensory innervation adjusts its location to maintain its greatest association with
surviving primary odontoblasts close to pulp horn tip
o With loss of primary dentin, innervation decreases and cytochemistry changes to reduce
expression of neuropeptides and neurotrophin receptors
o Innervation extends into most occlusal portion of pulp horn and then 0.1-0.2 mm of dentin
 Interactions between Sensory Fibers and Pulp
o All peripheral nerve fibers have definable set of interactions with local cells that are
specific for different functional subtypes.

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  Mechanoreceptors that end in cutaneous epithelia are associated with Merkel cells,
(special kind of neuroendocrine cell that secretes an array of neuroactive substances
essential to location and function of nerve endings
 In contrast, nociceptive endings have only a basal lamina covering and partial
Schwann cell support
 containing the sensory transducer in their peripheral endings
 Does not associate with special receptor cells
o Odontoblasts as special receptor cells has been proposed
 There are no synaptic or gap junctions connecting them with nerve terminals-
Byers!
 Other somatosensory receptors and nociceptors have sensory transduction
function (ability to convert tissue events into neural signals)
 Nerve endings extending into dentin-pulp border zone and into dentin have
little or no covering after leaving the cell-free zone
 Odontoblasts are predominant non-neuronal cells in peripheral pulp,
predentin and dentin
o special support functions for free nerve fibers would have to be
supplied by them
o Calcium currents in odontoblasts may be detected by nearby sensory
fibers
 may respond to current fluctuations
 In addition to ability to respond to hydrodynamic movement
of dentinal tubule contents
 Paracrine interactions of cells in pulp supports profound
influence between dental nerve fibers and odontoblasts
 Neuropeptide and neurotrophin receptors on
odontoblasts are consistent with proposal
 Nerve fibers prefer dentinal tubules with coronal
primary odontoblasts
 They avoid tertiary dentin or dead tracts
 They prefer special odontoblasts that make dentin that
lies directly under enamel Note: not odontoblast-like
cells
 Pulpal cells and pain mechanisms
o Current hypothesis
 Pulpal cells do not act as special sensory receptors as photoreceptors in eye or hair
cells in inner ear
 Do provide environment in which nerve fibers functions
 Odontoblasts may assume Schwann cell-like functions in peripheral pulp
and dentin
 Neurotensin-like immunoreactivity in odontoblasts suggests neuroendocrine
activity of odontoblasts
 Ion currents in odontoblasts related to dentinal matrix production and calcification
might also alter the ionic environment for nearby nerves

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  Pulpal cells and invading immune cells provide signals regulating sensory
phenotype
 Effect on functional activity of peripheral neurons including nociceptive
transmission
 Hypersensitive dentin may have central component
 Caused by altered signal processing in CNS
 Also include peripheral component caused by altered pulpal conditions
affecting nerve activity
 Examples: many enzymes and membrane receptors acquire
different functional levels in inflamed or acidic conditions

 Neural agents that affect pulpal cells and blood vessels

o *Sensory neuropeptides: CGRP, substance P, Neurokinin A, somatostatin, galanin
o *Sensory neurotransmitters: glutamate, Acetylcholine
o *Autonomic factors: norepinephrine, peptide histidine isoleucine, Acetylcholine,
neuropeptide Y
o *Schwann cell factors: NGF, GDNF, neurotrophin receptors

 Dentinal, pulpal, vascular, or immune agents that affect dental nerve function
o *Odontoblast-specific molecules (over 130 odontoblast-specific genes, some of which
would affect neural function, have been identified)
o *Neurotrophic factors: NGF, BDNF, GDNF
o *Inflammatory mediators: serotonin, histamine, Bradykinin, protanoids, cytokines
o *Cellular breakdown products: ATP, cyclooxygenase, oxidative radicals
o *Altered pH and its excitation or inhibition of molecular functions
o *Heat shock proteins
o *Somatostatin and endocrine factors
o *antinocicptive agents (e.g., opioid peptides, cannabinoids, adenosine)
o *Extracellular matrix factors (e.g., laminin and Metalloproteinases)
o *Ionic environment
o *Oxygen tension and interstitial fluid pressures

 “Neural” factors expressed by pulp

o *Neurotensin, nestin, protein gene product (PGP)
o *Tachykinin-precursor and receptor
o *Neurotrophin receptors: tyrosine kinase A (TrkA),
o *Neurotrophins: NGF, BDNF, GDNF
o *Nitric oxide

 G. Neuroanatomic Responses to Tooth Injury and Infection

o Neuronal responses to injury to pulpodentin complex
 Nerve fibers send rapid electrophyiologic signals to ganglion and central pain
pathways
 They release neuropeptides from peripheral terminals that regulate vasodilation and
leukocyte invasion of injury site

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  If sensory innervation removed prior to injury:
o Pulp is less able to defend itself
o Promote neurogenic inflammation
o Heal after pulpal exposure
 H. Nerve sprouting and cytochemical changes
 Reaction of dental sensory fibers to injury
o Extensive anatomic and cytochemical changes
in branches and endings
 1).In rat
o Initial depletion of neuropeptides due to release into pulp tissue
o Followed by increased neuropeptide content and sprouting of terminal fibers within 1
day post injury
 Response intensity and duration
dependent on severity of injury
 Innocuous stimuli: cold, heat and
vibration may cause changes in neurally regulated pulpal blood flow and
interstitial fluid pressure
 Gentle or superficial stimuli do not
usually injure dentin or pulp
 Can cause sufficient dentinal fluid movement to induce some pain
 Low-intensity electrical stimulation
able to induce pulpal responses and evoke nonpainful sensations
o Four different levels of injuries to pulpodentin complex
 Type I (shallow cavity prep, shallow scaling of cervical dentin, minor occlusal trauma, strong
orthodontic force, transient heat, or moderate hydrodynamic dentin injury
o Least damaging
o Cause transient change in pulp
o Dentinal damage easily fixed by reactive dentinogenesis (original odontoblasts survive)
o Extensive sprouting of neuropeptide-rich nerve fiber endings near injury return to normal
in few days to weeks
o Changes correlated with local production of NGF by fibroblasts near injury site
o Little or no invasion of leukocytes
o Local defense mechanisms sufficient

 Type II (deep cavity with some loss of pulpal tissue, heat stimulation of long duration/high intensity
and focal inflammation)
o Prolonged acute inflammation
o Invasion of leukocytes
o Local vascular responses
o Focal pulp loss
o Extensive sprouting of sensory fibers with enhanced neuropeptide contents
 Sprouting and CGRP upregulation
continue as long active inflammation not walled off by scar formation
o Formation of reparative dentin

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 o If infection prevented, larger injuries can have successful repair outcome
o Heals within a few months
 Type III (Enough pulpal damage or infection that local repair is not possible and irreversible pulpitis
ensues, large infected pulpal exposures, bacterial invasions at failed restorations, deep infected caries,
failure of pulp to make a scar barrier around and, coronal pulp destruction by heat or other excessive
stimulation) [If tooth has been denervated prior to injury, extent of damage is greater/necrosis faster]
o Irreversible pulpitis
o Persistent acute inflammation
o Advancing pulpal necrosis
o Elevated pulpal cell expression of NFG after dentinal injury
o Increased intensity of sensory nerves sprouting in surviving pulp near lesion
o Failure to repair dentin or heal the pulp
o Persists until treated
 Type IV (Injuries involve extension of infection into other tissues
o Tooth loss
o Persists until treated
 I. Distant placidity in the trigeminal ganglion and central endings after tooth injury
o Dental sensory nerve reactions extend into
 alveolar branches
 cell bodies in the trigeminal ganglion
 sensory endings in brain stem
 second-order neurons within CNS
o Responses at ganglion similar to those for spinal nerves responding to tissue inflammation
 increased expression of neurotrophin receptors
 neuropeptides
 voltage gated ion channels by neurons and increased expression of injury proteins
by satellite cells
o Effects on central pain pathways of tooth injuries
 persistent expression of c-Fos transcription factor by central neurons
 Indicates altered central pain pathway functions
 J. Neurophysiology of Pulpal Nociceptors and Dentinal Sensitivity
o Distinct groups of pulpal afferent nerve fibers classified based on morphologic
characteristics and conduction velocities are functionally different
 Activation may mediate different types of prepain and pain sensations
 Type of pain may vary according to
o Type of stimulus applied
o Type of neuronal fiber activated
o Condition of pulp
 Tissue injury and inflammation can sensitize and activate certain pulpal
neurons
o Pulpal inflammation has been associated with reduced thresholds to
external stimulation and spontaneous discharges of pulpal nerves
o May be due to synthesis or release of inflammatory mediators
 Application of cold to hypersensitive dentin in human subjects induces pain;
may be of high intensity

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  Acute pulpitis often reported as moderate to severe pain
 Pulpitis may proceed to total pulpal necrosis with minor or no symptoms at
all
 Pulpal nociceptor activation may be abolished by local inhibitory mediators
o local opioids
o cannabinoids
o somatostatin
o loss of functional terminals of these fibers
 Apoptosis
 Secondary to liquefaction necrosis
 Poor correlation between clinical pain symptoms and histopathologic
status of pulp
 Hyperalgesia is a perceptual event mediated by peripheral and central
pain mechanisms at the molecular level
 K. Sensory functions of pulpal nerves under normal conditions
o Two Classes (A- and C- fibers are functionally different)
 Unmyelinated
 A-fiber group is not uniform
 Some small slow-conducting (small) A-fibers seem sensitive to capsaicin
 Most faster fibers respond to hydrodynamic forces but not to capsaicin
 dentin sensitivity entirely dependent on intradental A-fibers
 can vary from sharp, stabbing to dull, aching, throbbing pain
 variation caused:
o by activation of different fiber types
o differences in firing patterns (temporal summation)
 Low-intensity electrical stimulation can produce non-painful stimuli
o A-beta fibers may mediate these prepain sensations
o Low electric threshold
o Thresholds overlap with those of A-delta fibers
 Increasing stimulation frequency at prepain intensities produces painful
sensations (Temporal summation in trigeminal nuclei)
 These findings suggest prepain and pain sensations mediated by same
afferent fibers.
 Only a small number of afferents is needed to evoke prepain and pain
o Clinical importance is that False Positive readings are possible if
few pulpal axons are functional
 A-beta and A-delta fibers activated by hydrodynamic mechanisms are
considered a discrete functional group classified as mechanoreceptors or
mechanical nociceptors.
o Trowbridge

 Pulpal C-fibers
o Polymodal (respond to several modes of stimulation)
o High activation thresholds
 Activated only if stimuli reach terminal endings inside pulp

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 o Respond to Histamine and Bradykinin
 May be activated in connection with pulpal inflammatory reactions
 Dull pain of pulpitis may be C-fiber activated
o Respond to capsaicin (selective irritant)
 Small nociceptive and neuropeptide-containing afferents
 Both A- and C- fibers respond to intense heating or cooling
o A- and C- fibers mediate different perceptual qualities of dental pain
o Sharp, with short latency, immediate, (within a few seconds) = A-fiber response to dentinal
fluid flow
o Dull, slow, radiating = C-fiber direct response to temperature change on nerve endings
 L. Neurophysiologic mechanisms of dentinal sensitivity
o Hydrodynamic mechanism
 Nociceptors in dentin-pulp border activated by fluid movement induced by
dentin stimulation (air blasts, probing, hyperosmotic fluid application).
 Unexposed dentin may also be stimulated but the capillary forces are not activated
and stimulus much weaker.
 Acid etching of drilled dentin increases sensitivity

 M. Sensory functions of pulpal nerves under conditions of pulpal inflammation

 Intense hydrodynamic stimulation may induce injury at dentin-pulp border.

o Aspiration of odontoblasts into dentinal tubules
o Injury of nerve endings
o Inflammation-induced elaboration of growth factors resulting in sensitization of intradental
nerves
 Morphologic
 Sprouting: increased density of endings
 Changes in regional sensitivity
 Phenotypic
 Increased neuropeptide expression
 Reduced threshold
o Serotonin activates and sensitizes A-fibers
o Prostaglandins mediate repeated heating sensitization
 Injury-induced inflammatory cascade probably signals pulpitis pain and acts to amplify dentinal
hypersensitivity
 Hydrodynamic stimulation
o a.Faster conducting pulpal afferents primarily respond
o b.Some small-diameter myelinated afferents affected
o c.Pulpal blood flow affected, indicating neurogenic vascular effects
o d.Silent A-delta fibers; (those activated only by intense heat or cold, whose receptive fields
are located deep in pulp); sensitivity enhanced in pulpal inflammation
o Functional significance to sprouting of sensory terminals
during inflammation
 1).Nerve sprouting reflected in size of receptive fields

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  a).Healthy teeth: gentle probing of exposed dentin reveals small receptive
fields
o i).Single spot
 b).Inflamed tooth: wide receptive field
o i).Whole dentinal surface
 c).Changes could be due to:
o i).Sprouting
o ii).Activation of normally “silent” terminals
o iii).Overlapping of receptive fields, enhancing spatial summation,
resulting in increased pain intensity
o f.Inhibitory effects of some mediators released in pulp after injury reduce or abolish
intradental nerve activity despite presence of other inflammatory mediators. May, in
part, account for lack of clinical symptoms in some inflamed teeth
 1)Endogenous opioids
 2).Somatostatin
 a).May reduce firing during injury

 Pain Mechanisms of the Pulpodentin Complex – Overview

o The pulp is innervated mainly by pain receptors
o Three steps to perception of acute pain:
 Detection: primary function of peripheral sensory (afferent) neurons
 Processing: thought to occur largely in medullary and spinal dorsal horns
 Perception: result of activity in more rostral brain regions such as cerebral cortex
 Transmission of Nociceptive Information to the Central Nervous System

 Odontogenic pain
o Stimuli to nociceptors that innervate dentinal tubules
 Noxious physical stimuli
 1).Thermal
 2).Chemical
 3).Mechanical
 4).Electrical (prepain sensations)
o Inflammatory mediators activate respective receptors
 Sensitize or depolarize nociceptors that innervate pulp
 Transmission pathways following activation of C and A-delta fibers
o Primarily via trigeminal nerves to trigeminal nuclear complex located in medulla
(trigeminal spinal tract nuclear complex)
 Trigeminal spinal tract nuclear complex includes
 1).Nucleus oralis
 2).Nucleus interpolaris
 3).Nucleus caudalis: (termed medullary dorsal horn because anatomic
organization similar to spinal dorsal horn and caudal extent merges with
cervical extent of spinal dorsal horn)
o Relay station where nociceptive signals are passively transferred to
higher brain regions

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o Plays important role in processing nociceptive signals and output to
higher brain regions
 i).Increased (Hyperalgesia)
 ii).Decreased (Analgesia)
 iii).Misinterpreted (Referred pain)
o Functionally the Medullary dorsal horn has five major processing
components related to processing nociceptive signals
 Central terminals of afferent fibers
 C and A-delta nociceptors
o i)).enter medullary dorsal horn via trigeminal
tract
o ii)).Central terminals of these fibers end
primarily in outer layers of medullary dorsal
horn
o iii)).Transmit Information by releasing
excitatory amino acids or neuropeptides
(substance P or CGRP)
o iv)).Antagonist to glutamate and substance P
reduces hyperalgesia or nociceptive
transmission. CGRP to lesser extent
o v)).Antagonists to NK1 class of substance P
receptors block hyperalgesia
o Note: Antagonists to NMDA and AMPA
classes of glutamate receptors are likely to
serve as prototypes for future classes of
analgesic drugs.
 Local circuit interneurons
 Regulate transmission of nociceptive signals from
primary afferent fibers to projection neurons
 Depending on neurotransmitter systems and
connections can enhance or suppress nociceptive
processing
 Projection neurons
 aa).Axons comprise output system for sending pain
signals to rostral (higher) brain regions
 bb).Cell bodies in MDH
 cc).Three major classes
o Nociceptive-specific receive sensory input
from nociceptive afferent fibers
o Low-threshold mechanoreceptive receive
input from non-nociceptors (A-beta fibers)
o WDR receive input from both noci and non-
noci fibers
 a)).Activation of intracellular protein
kinases PK-A and PK-C and elevation

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 of intra-cellular calcium thought to
facilitate responses to nociceptive
input
 b)).Also thought to modulate activity
of nearby cells via release of
protaglandins and NO gas
 dd).Major output pathway for projection neurons is
trigeminothalamic tract which crosses to contralateral
side of medulla and ascends to thalamus from which
additional neurons relay info to cerebral cortex via
thalamocortical tract
 Perception of pain thought to occur in
cerebral cortex where
disproportionately large area of cortex
receives input from orofacial regions
 Glia
 Supporting cells
 May participate in processing nociceptive input
 Respond to input and facilitate projection neurons by
release of cytokines such as interleukin 1β or TNF
 Terminals from descending neurons
 Modulate transmission of nociceptive information
 Endogenous analgesic systems
o Endogenous opioid peptides (EOPs)
 enkephalins,
 dynorphins,
 β-endorphin-related peptides
 Found at several levels of pain
suppression system
 May activate receptors at all levels of
neuraxis
 Antagonist naloxone significantly
increases pain perception during dental
procedures indicating relationship
between oro-facial pain and release of
EOP’s
o Cannabinoid system inhibits central terminals
of C fibers
 Hypoactivity may mediate forms of
chronic pain
 About 10 times more of these
recaptors in CNS may have profound
effects on modulating pain)
 May inhibit peripheral terminals of unmyelinated
nociceptors

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 o Trigeminal sensory neurons provide input to all three plus other
regions
 1). Cervical dorsal spinal cord
 2). Reticular formation
 3). Solitary tract nucleus

 NOTE: In addition to detection and transmission of noxious stimuli to dorsal horn where processing
takes place the pattern of peripheral input plays important role in mediating and modulating pain
perception.
 Classic “gate-control” theory in which activity of larger-diameter low-threshold mechanoreceptors is
thought to reduce pain perception is basis for TENS. Studies suggest that TENS may not provide
substantial control of dental pain.
 Other studies of the concept that “pain suppresses pain” has provided support (ischemic muscle pain
reduced pain from irreversible pulpitis as well as reducing area of referred pain) TMJ pain not
similarly reduced. Thus central modulation regulating pulpitis pain is different from systems
regulating TMJ pain.

 Mechanism of Dental Pain Caused by Inflammation

 Pulpal C nociceptors
o 1. Predominant role in inflammatory pain arising from pulp and
PA tissue
o Hypothesis supported:
 1). By distribution of C fibers in pulp
 2). Responsiveness to inflammatory mediators
o a). Bradykinin
o b). Capsaicin
 3). Perceptual qualities of pain associated with
pulpitis and C fiber activation
 b. Responses to inflammation or infections involves
coordinated release of multiple classes of inflammatory
mediators
 1). Terminals of nociceptive primary afferents
detect presence of
inflammatory mediators
 2). Receptors are synthesized in afferent fiber’s cell
body and transported to
periphery
 3). If concentration of mediator reaches threshold
concentration receptor
would be activated,
activating neuron
o a). Membrane depolarized
 i). Signal conducted to CNS
o b). Membrane sensitized
 i). Spontaneous depolarization
 ii). Reduced threshold for

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 depolarization
 iii). Increased after-discharges to

supra-threshold stimuli
 4). Some mediators activate terminals
o a). Bradykinin
 5). Others potentiate effects of some mediators
o a). Prostaglandins
 i). Prostaglandin E2 increases

stimulatory
effect of Bradykinin
 6). Combinations are important
 7). Others may produce persistent effects
o a). NGF injection can evoke pain and
allodynia for up to 1 month
o b). contributing to altered pain states of
allodynia and Hyperalgesia
 8). Mechanisms of mediating actions of inflammatory
mediators and drugs on sensory neurons
o Mediators whose receptors couple withGq
guanosine triphosphate binding protein
(including Bradykinin) lead to activation of
protein kinase C pathway of second
messengers, activating nociceptors
o Those that couple with Gs guanosine
triphosphate binding protein (including
prostaglandins) activate protein kinase A
pathway of second messengers sensitizing
nociceptors
o Those that couple with Gi guanosine
triphosphate binding protein (includes opiates,
cannabinoids, and adrenergic agonists) tend to
be analgesics.
 A-delta fibers
o Implicated in mediating dentinal sensitivity
 Hypothesis supported:
 Distribution
 Responsiveness to stimulation of dental tubules

 Allodynia and Hyperalgesia
o Allodynia is a reduction in pain threshold so that previously non-noxious stimuli are
perceived as painful
 Wearing a T-shirt over sunburned skin causes pain
 Percussion of a tooth with acute inflammation of PDL with mirror handle

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  Mastication
 Throbbing pain associated with systolic blood pressure
 Normal physiologic temperature activates peripheral neurons
o Hyperalgesia is an increase in perceived magnitude of painful stimulus
 slapping the sunburned skin
o Peripheral mechanisms of allodynia and hyperalgesia
 Hyperalgesia due to both peripheral and central mechanisms
 Concentration and composition of inflammatory mediators can lead to activation or
sensitization of nociceptors
 Concentration must be high enough to permit binding and activation of
receptor
 Prostaglandin E2 levels in irreversible pulpits than in normal
control tooth
 Heat-induced inflammation of pulp sensitizes afferent fibers
by local release of prostaglandins
 Can be caused by preps with insufficient water spray
 Can be blocked by pretreatment with NSAIDs
 I & D or pulpectomy may reduce pain by reducing concentrations of
mediators as well as tissue pressure
 Peripheral afferent fibers respond to mediators such as NGF by increasing protein
synthesis of substance P and CGRP and sprouting terminal fibers
 Sprouting increases density of innervation and may
contribute to increased pain sensitivity in chronic pulpal or
periradicular inflammation?
 Tetrodotoxin (TTX)- resistant sodium channels may be formed due to the
synthesizing of other proteins in response to inflammatory mediators
 1). TTXr on sensory neurons (C-fibers)are poorly
blocked by local anesthetics
o Takes about 4 X more lidocaine to block than
typical TTX-sensitive ion channels
o May be cause of “Hot Tooth” syndrome
 After block, patient has profoundly
numb lip and tongue but
manipulation of pulp is painful.
o *Bupivicaine found to be more effective in
blocking TTXr channels.
o *Pinto, Scholtz
 A-beta fibers thought to be low-threshold mechanoreceptors that do not
ordinarily conduct nociceptive signals.
 With inflammation they begin to express substance P and
develop new central terminals in dorsal spinal cord,
innervating regions that contain nociceptive neurons
 Other studies show sympathetic fibers activating C fibers after certain forms
of tissue injury

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  Not all mechanisms equally active in all pain states, leading to concept of
mechanistically based pain diagnoses
 Central mechanisms of allodynia and Hyperalgesia
o Central sensitization is increased excitability of central neurons (major mechanism of
hyperalgesia)
 Results from barrage of impulses from C nociceptors
 Central release of excitatory nuerotransmitters: glutamate and substance P
o Leads to activation of central receptors for glutamate (NMDA and
AMPA receptors) and NK1 receptor for substance P
 Under these conditions, stimulation of normally low-threshold A-Beta fibers
now produces a much larger response (allodynia)
o Importance of concept is that it implies dynamic responsiveness of the CNS to peripheral
input
 “Same stimulus does not always produce the same response”
 Application of mustard oil to pulp in max. molar of rat
 5 X increase in discharge rate of nociceptive-specific neurons in nucleus
caudalis
 Production of central sensitization with (20 minutes later) enhanced
response to light tactile stimuli applied to maxillary skin
 Can be blocked with pretreatment antagonist to glutamate receptor.
 3). Pulpotomy can result in expansion of receptive
field sizes and increase in spontaneous activity in
nucleus oralis
o Central terminals of afferent fibers continue increased release of
CGRP even after removal from the animal
 Central mechanisms of hyperalgesia or allodynia can persist for some time even in
absence of peripheral input.
 “Presence of preoperative pain is a risk factor for the occurrence of postendodontic
treatment pain”.
o Consider higher levels of pain control
o Referred Pain is condition in which pain is perceived to be localized in one region but is
caused by nociception from another area
 Mechanisms of referred pain
 Peripheral: Branching of axons that innervate different structures and axonal
reflexes
 IV. Mechanisms of Dentinal Hypersensitivity
o Hydrodynamic theory of dentinal hypersensitivity
o Effects of pulpal inflammation on dentinal sensitivity

 Common Features of Odontogenic and Nonodontogenic Dental Pain

o Odontogenic dental Pain

 Common features of odontogenic dental pain

Presence of etiologic factors for an odontogenic origin of pain (eg. Caries, leakageof

17
restorations, trauma, fracture)
Ability to reproduce chief complaint during examination
Pain reduction by local anesthetic injection
Unilateral pain
Pain qualities: Dull, aching, throbbing
Localized pain*
Sensitivity to temperature*
Sensitivity to percussion, digital pressure*
*Diagnosis-specific
o Pain of pulpal origin often difficult to localize
o Pain from acutely inflamed periradicular tissue easier
 Absence of a common feature should prompt clinician to consider other possibilities
 Inability to reproduce patient’s chief complaint should raise red flag.
 Clinicians need to understand that the pain site does not necessarily equate to the
pain source. Some simple tests (such as muscle/joint palpation or local anesthetic
injections) can help practitioners identify the actual source of the pain.
 Murray
o Anatomical & Regional Evaluation- must test all CN for any deficit
o Sensory pathways
 Touch sensation accomplished with a light touch
 Pain sensation accomplished with a brief pinprick
 CN V– forehead V1, cheek V2, and tongue V3
 CN VII– area of external auditory meatus
 Special Senses: CN I: smell, CN II: sight, CN VIII: hearing
o Motor functions
 Having the patient follow a moving object with their eyes; tests CNs III, IV, and VI
 Raising the eyebrows, closing eyes and lip puckering; tests the CN VII Tongue
movement determines the CN XII
 Saying “Ah” tests CN IX
 Gag reflex tests CN X
 SCM tests CN XI

 II. Mechanisms of Nonodontogenic Dental Pain

o Frequency of Non-odontogenic pain after NSRCT- Systematic Review/Meta-analysis
 3.4%
 56% was from non-odontogenic causes
 Nixodorf
o Prevelance of peristant pain after NSRCT 3-5 years and it’s impact on QOL:
 3.1%
 Vena
o A single “snapshot” pain rating may not be an accurate predictor of a patient’s true pain
intensity due to the fact that most pain patients state that they have good and bad days
regarding their level of pain.
 Jensen
 Referred Pain

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 o Most common
o Reffered: pain felt in an area innerved by a neuron different from the one that mediates the
primary pain
 Projected: pain felt in the peripheral distribution of the same nerve that mediates the
primary nociceptive input.
 AXIS I: SOMATIC: SUPERFICIAL PAIN
o Pain is bright, stimulating
o Relief by topical
o Convergence hypothesis:
 Certain afferent sensory neurons may innervate different tissues
 Their central terminals converge onto same second-order projection neuron located
in trigeminal nuclear complex: converge onto projection neurons
 More primary afferents entering the CNS than there are second-order neurons to
carry the impulses
 Several primary neurons must synapse with a single second-order neuron:
phenomenon can cause misdirected relay of nociceptive input and can lead to
perception errors.
 50% of neurons in the nucleus caudalis exhibit convergence of sensory input
from cutaneous and visceral structures
o Sessle ‘56
 Anatomic considerations include the sharing of the trigeminal neurons with
cranial nerves VII, IX, X, XI and XII and the upper cervical nerves C1, C2,
C3
o Austin
 Pain perception of “site” of pain differs from “origin” of nociceptor activation
 Heterotropic pain: site and source differ
 Primary pain: site and source are the same.
o More intense pain has greater probability of referral to other regions
Axis I- PHYSICAL :SOMATIC PAIN:
 Stimulation of nociceptors due to chemical, thermal, mechanical events
 Processes involved in nociception
 Transduction- converted into AP
 Perception- central processing
 :DEEP PAIN:
o :MUSCULOSKELETAL origin: Muscle pain, TMJ pain, periodontal pain, dental pain of
periodontal origin
 Myofascial pain/TRIGGER POINTS: Temporomandibular dysfunction
 Etiology: Unknown; (Gate-control theory: MELZAK & WALL takes into
account physiological summation, central summation, patterning,
modulating input, and influence of AXIS II)
o No genetic component contribution found
o Environmental factors exert major influence:
 Tooth clenching (related or not to grinding), head/neck
trauma, anxiety, and female gender may contribute to chronic
MFP

19
  Velly
o Relationship of stress upon the hypothalamic-pituitary-adrenal
(HPA) axis
 Depletion of hormones and neurotransmitters results in stress
and can lead to many disorders, including TMD
 Auvenshine
 Sensitization, neuroplasticity of circuits, and behavior
sensitization
 Stohley
 Disturbed sleep, depression, anxiety, menstrual symptoms
 Gay
 Differential diagnosis: described as deep, dull, aching pain of diffuse
localization
o Diagnosis of NODP from muscle pain rather than tooth pain often
found when:
 pain is diffuse and not restricted to tooth
 palpation of trigger points or muscles exacerbates pain
 pain not relieved by intraoral local anesthetic block
 there is restricted jaw movement
 pain not altered by thermal stimuli
 NON-pulsating
 Muscles typically involved
o Superior belly of masseter (maxillary posterior teeth)
o Inferior belly of masseter (mandibular posterior teeth)
o Anterior digastric (mandibular anterior teeth)
o Temporal (maxillary anterior or posterior teeth)
 Gay: those with masticatory muscle pain report an
accelerated rate of fatigue not a constant fatigue.
 Common regions of palpation-induced referred pain: According to Wright
o Cheek (21%)
o Ear (14%)
o Forehead (14.5%)
o Teeth (11.6%)
 A case is presented in which a muscular trigger point pain
mimicked the presentation of a tooth with endodontic
involvement.
 Reeh
o EMG activity from neck
 Commonly referred to jaw muscle pain, but not vice versa
 Svennson:
 According to Wright
o 85% TMD patients experienced referred pain from palpation of
trigger points and other selected masticatory structures.
o Molars received referred pain from palpation of muscles or trigger
points most often

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 o Masseter muscle most common source of referred pain
o Frequency of referred pain to maxillary and mandibular teeth is
about the same
o Palpation of masseter, lateral pterygoid and temporal muscles and
TMJ produce a more than 10 fold (132/9) reports of referred pain as
opposed to medial pterygoid, coronoid process, trapezius, splenius
capitus, sternocleidomastoid, anterior digastric and posterior
digastric.
 Treatment modalities
o Physical self-regulation training by Carlson for TMD pts incuded
seven disciplines
 Splints
 Posture training
 Sleep
 Relaxation training
 Physical activity
 Nutrition
 Diaphragmatic breathing strategies
 diaphragmatic breathing strategies that are common
to many reported self-regulation strategies may be
based on restoring normal pH, establishing oxygen-
carbon dioxide balance, and reducing neuronal
activity.
o Carlson: for masticatory muscle pain
o :VISCERAL origin: pulpal pain, vascular pain, ENT pain, ocular pain
 PULPAL PAIN
 BARODONTALGIA:
o Source is vital tooth or previously treated: pulpal origin
o Site: Mx sinus from changes in pressure
 Senia
 CARDIAC JAW PAIN

 ENT PAIN: SINUSITIS/RHINOSINUSITIS
 AURICULOTEMPORAL
 NEUROVASCULAR ORIGIN
o Migraine
 Migraine with aura, classic migraine, is risk factor for stroke –
should be referred
 Migraine without aura is termed common migraine
o Etiology (unknown)
 Hypothosis of vasodilation of cephalic and cerebral arteries with
activation of sensitized perivascular nociceptors has experimental
support.
 Convergence of trigeminal nociceptive inputs arising from
craniofacial structures as a result of TMD may influence the

21
 activation of trigeminovascular system, since these
nociceptive inputs convey in the Trigiminal nucleus caudalis
where intracranial inputs do:
o Extracranial input: masticatory muscles, TMJ,
cervical muscles
o Intracranial input: dural blood vessels and higher
centers
 Graff-Radford
o Genetic factors
o Stress
o Dietary factors
o Altered sleep patterns
o Menstruation
 Differential diagnosis
o Not restricted to tooth:
o Unilateral dull, throbbing pain quality
o Unrelieved by diagnostic intraoral local anesthesia
o Not altered by intraoral thermal stimuli
o Increased by physical activity
o Often associated with nausea, emesis, affective changes in mood,
and sensitivity to light or sound
o Most often in females less than 50 y. o.
 Treatment
o Prophylactic or abortive drugs.
 Sumatriptan and other serotoninergic agents that block 5HT1
or 5HT3 serotoninergic receptors
 Gabapentin
 Injection of botulinum toxin
 Ergotamine largely replaced because of side effects
 Cluster headache (Sluder neuralgia) (Unknown) may be episodic
vasodilation activating perivascular

Axis I- NEUROPATHIC:
 :NEUROPATHIC:EPISODIC:
o Trigger points, not chronic
 PAROXYSMAL PAIN or intermittent pain
 NEUROVASCULAR PAIN (overlaps with deep visceral)
o :PROXYSMAL PAIN:
 TRIGEMINAL NEURALGIA(TIC DOULOUREUX)
 Etiology: unclear:
o In rats, compression of trigeminal nerve is a hypothesis
o In humans, tortuous or aberrant blood vessels compressing the
trigeminal root has been implicated in the syndrome
 Symptomatic TN
 Differential diagnosis:

22
 o Pain quality and duration: unilateral, severe, shooting, electric-like
pain lasting only a few seconds affecting >1 division of CN V
 Pretrigeminal neuralgia
 Etiology: thought to be early form of trigeminal neuralgia
 May experience dull, continuous, aching pain prior to
paroxysmal attacks and can be relieved with
medication to disrupt pain pathway.
o Fromm
o Trigger point to gentle touch along distribution of nerve may evoke
attack
 65% located intra-orally, no correlation between trigger
points for Idiopathic TN and frequency of dental procedures
 De Siqueira
o Pain not restricted to tooth
 Many have hx of several NSRCT:
 Francica: 3 key features to differentiate from
odontogenic pain
 as duration of Idiopathic TN went up, so did the
number of patients that underwent dental procedures
o De Siqueira
o Pain not relieved by LA unless trigger is in area
o Pain not altered by intraoral thermal stimuli
o Frequency in trigeminal division:
 mandibular>maxillary>> ophthalmic
 Treatment
o Pharmacologic: Carbamazepine, gabapentin, baclofen, phenytoin,
Tegretol, and valproic acid
o Anesthetic injections into area of trigger point
o Mucosal administration of capsaicin
o Rhizotomy
o Nerve decompression:
 Intracranial microvascular decompression
 Also for glossopharyngeal neuralgia
o Horowtiz
 peripheral nueroectomy
o Better prognosis than atypical facial pain
 Turp & Gobetti
 :NEUROPATHIC:CONTINUOUS PAIN:
o Chronic pain,
o Nerve injury: from trauma from syringe needs or damage during surgery
 Nerve injury is associated with inflammation and release of nerve growth factor
(NGF) from cells participating in the repair response, including mast cells
 Neuritis
 NGF stimulates growth of sympathetic nerve tissue

23
 
Ineffective healing of a nerve due to excess production of NGF and benign
overgrowth of nerve tissues
 Develops secondary to neural injury or irritation
o Neuroma
o Damage to nerves system itself cause the neuropathic pain, two types:
 PERIPHERAL: damage to peripheral nerves
 Relieved by local
 CENTRAL : damage to the brain/brain stem/spinal cord
 Not relieved by local
o :PERIPHERALLY MEDIATED:
 Neuritis
 Atypical odontalgia: also has a component with :CENTRALLY MEDIATED:
 Idiopathic pain
 Phantom tooth pain
o New term for this is Chronic Continuous Dentoalveolar Pain
(CCDP)
 Greene & Murray
 Deafferentation pain (Traumatic Neuroma)
 Etiology: (unknown) often associated with trauma or inflammation in region
o Deafferentation Hypothesis (neurological response to nerve injury):
 Organization and activity of centeral and peripheral nerves
change and can result in:
 Chronic pain
 Paresthesia
 Dyesesthesia
 Strong evidence for CCDP (not psychological)
 Marbach
 Continuous pain which is the result of disruption of normal
afferent nerve fibers resulting spontaneous activity and
ectopic impulses being transmitted to the brain (Woda)
 nociceptor sensitization
 sprouting of adjacent afferent fibers
 phenotypic changes and ectopic activity from the
nociceptors
 central sensitization possibly maintained by ongoing
activity from initially damaged peripheral tissues
o Higher order neurons involved
 Spontaneous pain
 List
o Activation of the glia in the spinal cord which
releases proinflammatory cytokines
 Driving force for pathological pain:
 Watkins
 sympathetic activation of afferents

24
 o SYMPATHETICALLY MEDIATED
PAIN:
 partially
 Vickers
 alteration of segmental inhibitory control
 hyper/hypoactivity of descending controls
o Vascular hypotheses
o Psychosocial etiologies
o Multifactor/polymodal
 Vickers
 10 X more prevalent than trigeminal neuralgia.
 Differential diagnosis (Woda)
o Diffuse pain
o Not always associated with tooth (may be edentulous area)
o Almost always continuous pain: no paroxysmal
o Quality often described as dull, aching, throbbing, or burning
sensation
o Local anesthetic effect mixed:
 Significant but not complete relief
 List
o Often lasts more than 4 months:
 4.4 years
 Bates
o Not altered by thermal stimuli
 Case report of spontaneous odontalgia aggravated by cold
food and diagnosed as primary vascular orofacial pain.
Treatment with beta blockers and amitriptyline
 Czerninsky
o Patients often report history of traumas or ineffective dental
treatment in the area:
 Post-surgical neuralgia:
 Damage to IAN n. after third molar extractions was 0-
23%
o Eisenberg
 May include up to 3% of patients receiving pulp extirpation,
extractions, and rarely IANB
 Battrum & Gutmann
o Gender/Age predilection:
 90% female and middle-aged
 Bates
 Estrogen hormone as possible risk factor
 Psychological factors
 Menopause occurance of osteoporosis
o Risk factor for NICO lesions
 Woda

25
 
Treatment (difficult)
o Since these patients have often had multiple unsuccessful
interventions to relieve their pain, there is likely to be an overlying
psychological component. Additionally, Pharmacologic treatments
may take extended time periods to achieve pain relief. The patient
must be made aware of these facts and trust must be gained.
 Tricyclic antidepressants
 Bates
 Capsaicin applications
 Sympathetic block (eg. Stellate block)
 Vickers
 Systemic lidocaine or lidocaine patch.
 Local anesthesia:
o RCT showed significant but not complete
relief
 List
 Topical EMLA (mixture of lidocaine and prilocaine)
shows immediate relief
o Vickers
 Treatment with beta blockers and amitriptyline
 Case report of spontaneous odontalgia aggravated by
cold food and diagnosed as primary vascular orofacial
pain.
o Czernisky
 Loads of understanding and caring
 Neuralgia-inducing cavitational osteomylitis/osteonecrosis (NICO)
 Chronic orofacial pain (TN or atypical facial neuralgia) caused by
cavitational defects in jaws
o Chronic osteomyelitis
o Bouquot
 Etiology (proposed) Controversial and not supported by science.
o Bone cavities containing chronic inflammation or necrosis from
bacterial osteomyelitis or vascular pathosis following tooth
extraction
 Treatment
o Surgical debridement of bone cavities and antibiotic treatment
o :CENTRALLY MEDIATED:
 Complex Regional Pain Syndrome
 Systemic disorder
o Disorder interaction with pulpal or periradicular nociceptors but not
derived from dental pathoses
 Dental treatment may be ineffective in reducing pain
o Malignant neoplasia
o Diabetes
o Lyme disease

26
  Multisystemic inflammatory disease caused by tick bite
 Borrelia burgdorferi
 Macular rash after a month
 Neuritis, neuralgia, facial palsy, fatigue, and malase
 Rhodus
o Sickle cell anemia
 May signal impending sickling crisis
 Developmental
o Eagle’s Syndrome
 Calcified Styloid hyoid ligament: >30mm
 Difficulty swallowing and elicited by turning head or neck
 Follows path of carotid aretery
 Sivers
 Chronic Burning Pain
 Burning Mouth Syndrome can also be :PERIPHERALLY MEDIATED:
 Occlusal Dysesthesia can also be :PERIPHERALLY MEDIATED:
 impairment of any sense, especially of the sense of touch.
 painful, persistent sensation induced by a gentle touch of the skin
 Trigeminal Dyesthesia
o With headaches:
 Chiari Malformation should be considered
 Storrs
 Postherpetic Neuralgia
 Caused by the recurrent form of the varicella zoster virus, referred to as
herpes zoster or shingles
 Occurs unilaterally:
o Initial prodromal phase
 Prodromal phase presents with deep, burning, boring ache
involving superficial mucosal and cutaneous tissues and also
the bones of the maxilla and mandible.
 May persist for weeks to years
 :SYMPATHETICALLY MEDIATED PAIN:
 Should be added to differential
 Fristad
o Followed by vesicular phase (hours or days)
 Can follow almost any dermatone, not just CN V
o Bennett
 AXIS II: PSYCHOLOGICAL CONDITIONS
 Psychosocial or behavioral factors can influence a patient’s interpretation and report of pain
o Environmental and experiential factors may skew a patient’s reports of pain
o Skilled clinician must interpret patient’s pain report as well as realize that their own
psychosocial and cultural factors may influence how they interpret a patient’s pain report
 MOOD DISORDERS

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