Neurobiology of Temporomandibular Joint

Pain: Therapeutic Implications

Ernest A. Jennings, Michael C. Williams, Vasiliki Staikopoulos, and
Jason J. Ivanusic
Persistent pain is the main reason for patient presentation with temporomandibular joint (TMJ) disorders. The pain is thought to result, at least in
part, from sensitization of trigeminal sensory neurons that innervate the
TMJ region. Sensitized sensory neurons can be hyperexcitable, responding
both more readily and more vigorously to peripheral stimuli. At a cellular
level, it is the distribution and function of ion channels and receptors that
determine neuronal hyperexcitability. Thus, these ion channels and receptors are potential targets for the development of novel therapeutics. In this
review, we will explore the role of specific ion channels and receptors
that are actively being investigated in preclinical studies, focusing on
inflammatory-induced pain of the TMJ, and comment on the therapeutic
potential of pharmacological manipulation of these channels and receptors in the treatment of pain associated with TMJ disorders. (Semin
Orthod 2012;18:63-72.) 2012 Elsevier Inc. All rights reserved.

emporomandibular joint (TMJ) disorders

can affect up to 10% of the population,1
and pain is the predominant symptom.2 TMJ
disorders have been classified as myofascial in origin or resulting from disk displacement, osteoarthritis, or arthralgia.3 Signs of inflammation within
the TMJ or adjacent tissues and pain accompany
most of these disorders.4-6 The pathophysiology
and etiology of craniofacial muscle pain are not
sufficiently well characterized to allow causal treatment,7 emphasizing the importance of symptomatic treatment.
Persistent pain associated with TMJ disorders
is the main reason for patient presentation, and
it greatly affects their quality of life.2,8-10 The
presence of allodynia, hyperalgesia, and pain
referred to sites other than the TMJ are common features of the pain profile in humans and

Department of Anatomy and Cell Biology, University of Melbourne, Parkville, Victoria, Australia; School of Medicine and Dentistry, James Cook University, Cairns, Australia.
Address correspondence to Ernest A. Jennings, PhD, School of
Medicine and Dentistry, James Cook University, PO Box 6811,
Cairns, QLD 4870, Australia. E-mail: ernest.jennings@jcu.edu.au
2012 Elsevier Inc. All rights reserved.
1073-8746/12/1801-0$30.00/0
doi:10.1053/j.sodo.2011.10.003

are thought to result from sensitization of neurons in the trigeminal system (see the following
text). Inflammation of the TMJ can produce
pain with these characteristics in experimental
animals11-15 and can also induce sensitization of
trigeminal neurons.16 It is clear that inflammation is relevant to the pathophysiology of many
TMJ disorders.
In this review, we will explore the role of
specific ion channels and receptors (Fig. 1) that
are actively being investigated in preclinical
studies, focusing on inflammatory-induced pain
of the TMJ and comment on the therapeutic
potential of pharmacological manipulation of
these channels and receptors in the treatment of
pain associated with TMJ disorders. Ion channel
functions (and the receptors mediating large
ion fluxes) are major determinants of neuronal
excitability, and currently, ion channel blockers
comprise 6.5% of the top 200 prescribed drugs
and are a major target for new drug development.17
Inflammation-induced sensitization can affect
neurons at different levels of the trigeminal nociceptive pathway. Sensitization of primary afferent (peripheral) neurons is often referred to as
peripheral sensitization, and sensitization of sec-

Seminars in Orthodontics, Vol 18, No 1 (March), 2012: pp 63-72

63

64

Jennings et al

Figure 1. Schematic diagram of temporomandibular joint afferent with enlarged section showing ion channels/
receptors discussed in review. Ion channel or receptor openings (or closing) that result in a net increase in
inward current cause neuronal depolarization, and thus, increased excitability. Peripheral sensitization induced
after inflammation to joint afferents results in altered activation thresholds such that greater inward currents
flow through channels and neurons are more easily excited.

ond-order (or higher) neurons is referred to as

central sensitization. In this review, we will concentrate on peripheral sensitization.

Peripheral Sensitization and the Primary

Afferent Neuron
Trigeminal afferent nerves innervate the majority structures in the head, including the TMJ.6,18
Based on conduction velocity studies, TMJ afferents are reported to be small-diameter nociceptors with approximately half thinly myelinated
A fibers and half unmyelinated C-fibers.19 Sensory signals are transduced at the periphery,
evoke action potentials in sensory neurons, and
travel along peripheral nerves toward the central
nervous system (CNS), where sensory information is passed to higher centers. The peripheral

sensory neurons in both the trigeminal and spinal/dorsal root systems are called primary afferent
neurons, as they are the first in the somatosensory
pathway. They have an unusual pseudounipolar
morphology, having both peripheral and central
terminals and a cell body located in between.20
The cell bodies of spinal primary afferent neurons
lie in the dorsal root ganglia (DRG), whereas
those of the trigeminal primary afferent neurons lie in the trigeminal ganglia (TG). Primary afferent neurons convey many modalities
of somatosensory information, including noxious and innocuous stimuli. Combined functional and histological studies have identified
that most information about noxious stimuli is
relayed to the CNS by nociceptive neurons
classified as small-diameter C type (associated
with unmyelinated, slowly conducting axons)

Neurobiology of Temporomandibular Joint Pain

and A type (associated with thinly myelinated

axons with intermediate conduction properties).21,22
As primary afferent neurons are the first neurons in the somatosensory pathway, they present
ideal therapeutic targets. Plasticity in peripheral
nociceptors is integral to both the development
and maintenance of plasticity in the CNS, an
important mechanism of many pain states,23 including those with TMJ disorders.24 Thus, attenuation of a peripheral neuronal barrage after
noxious insult may result in a reduction in hyperexcitability at higher centers in the pathway.25 Furthermore, although not in the classical
textbooks, there is a growing literature describing crosstalk between neuronal cell bodies in
sensory ganglia20 and gap junction communication that involves the satellite glia that completely envelop neuronal cell bodies in sensory
ganglia.26 This less well-studied communication
between primary afferent neurons is likely to
contribute to peripheral sensitization.
In the case of inflammation, for example,
after injury, peripheral sensory neurons can become sensitized, which involves increases in
spontaneous activity and decreases in activation
threshold.27 These changes in excitability allow
for action potentials to fire more easily and rapidly, and are likely to reflect changes in ion
channel expression (distribution or subcellular
expression) or function (biophysical properties
such as opening kinetics). It is therefore important to understand the action of ion channels
and how they may directly influence nerve conduction and excitability, thus providing a potent
target for potential therapeutic interventions.

Receptors and Channels

Voltage-Gated Na and K Channels
Voltage-gated Na channels (VGSCs) are a logical potential therapeutic target in the treatment
of pain, and these are the principle targets of the
widely used local anesthetics in dental clinics.28
They are logical targets for blocking sensory
neuronal activity, as activation of VGSCs is critical for the generation and propagation of neuronal action potentials.29 For example, Park et
al30 showed that eugenol, a local analgesic frequently used in dentistry, reversibly inhibited
action potential generation and VGSC currents

65

in trigeminal ganglion neurons, suggesting that

eugenol functions through peripheral blockade
of nerve conduction of nociceptive input via
inhibition of VGSCs. In addition, blockade of
VGSCs has been shown to attenuate the pain
associated with nerve injury and inflammation in
both humans31,32 and animals.33,34
At least 9 channels have been cloned (NaV1.11.9) and are functional as a single pore-forming
subunit with associated subunits, which can
modulate the function of the -subunit.35,36 Although local anesthetics block all VGSCs, at least
2 of them (NaV1.8 and NaV1.9) are resistant to a
neurotoxin called tetrodotoxin (TTX) and are
thus named TTX-resistant Na channels (TTXR). Many of the VGSCs are found in sensory
neurons as well as other parts of the body (although primarily in the nervous system); however Nav1.7, Nav1.8, and Nav1.9 are predominantly found in small-diameter primary afferent
sensory neurons reviewed by Lai et al, and thus
are potential therapeutic targets for the treatment of pain because most nociceptors are
small-diameter primary afferent neurons.
Because of the lack of drugs for the pharmacological manipulation of specific VGSCs in
small-diameter nociceptive neurons, initial studies examined receptor protein localization (using immunohistochemistry) and correlated this
with the functional characteristics (using electrophysiology) of sensory neurons. The studies
have indicated that Nav1.7,37 Nav1.8,38,39 and
Nav1.940 are located in most C-type and A-type
nociceptive DRG neurons and thus contribute to
their membrane properties.
Another approach to investigation of VGSCs
involves examining knockout mice lacking
Nav1.7,41 Nav1.8,42,43 or Nav1.9.44 This demonstrated that behavioral changes induced by inflammatory mediators are reduced or absent in
knockout animals compared with wild-type controls. Importantly, none of these mice have altered responses after nerve injury, highlighting a
key difference in the biology of inflammatory
and neuropathic pain. It is widely acknowledged
that interpretation of results from knockout animals is complicated, as there are likely to be
compensatory changes in expression of other
channels. However, data from electrophysiological studies also implicate VGSCs in inflammatory hyperalgesia. For example, after peripheral
inflammation, there is significant upregulation

66

Jennings et al

of Nav1.8 and the TTX-resistant current in DRG

neurons.45 In the trigeminal system, an inflammatory stimulus delivered directly to the TMJ
results in a decrease in TTX-sensitive Na currents and increase in the slow inactivating TTXresistant current, thought to be Nav1.8.46 In
agreement with these results is another study in
which inflammation is induced in the upper lip
by administering complete Freunds adjuvant
(CFA, an inflammatory stimulus), resulting in an
upregulation of Nav1.8 protein and mRNA, but
not Nav1.9 mRNA, 1-2 weeks after administration.33 This same study showed that the hypersensitivity induced by the inflammatory stimulus
could be attenuated by delivery of Nav1.8 antisense oligodeoxynucleotide to the TG, which
acts to block Nav1.8 protein production. In addition, acute application of inflammatory mediators, such as prostaglandin E2 (PGE2), results in
an increase in neuronal excitability in primary
afferent neurons47 and further alters the activation voltage of TTX-resistant Na channels, so
that they are activated closer to resting membrane potentials and thus contribute to action
potentials firing more readily.47-49
Because of the critical role of Na channels in
neuronal excitability, preclinical studies have
shown that more prolonged regional anesthesia
could be achieved when local anesthetics are
delivered in biodegradable microspheres, allowing sustained release.50 However, nondiscriminant blockade of VGSC results in neural paralysis, which apart from regional anesthesia, rarely
serves a clinical function. Other preclinical studies have demonstrated a more specific blockade
of Na channels. An elegant study demonstrated
prolonged blockade of Na channels selectively
on primary afferent fibers with TRPV1 receptors,
as they were activated by capsaicin (the active
ingredient of chili peppers).51 These investigators exploited a distinctive property of TRPV1
channels, that an appropriate agonist concentration causes the channel pore to dilate, thus allowing access to compounds of larger sizein
this case, the quaternary derivative of lignocaine
(QX314), which blocks Na channels, acting at
an intracellular site.51 In a subsequent study,
these investigators have demonstrated that
lignocaine (which also has agonist activity at
TRPV1 receptors) is also effective at allowing
QX314 into neurons when the 2 agents are coadministered.52 This approach has obvious clin-

ical benefits, as there is no requirement to stimulate pain fibers to block them with QX314.
Another approach demonstrates some potential
for selective blockade of specific Na channels.
The O-conotoxin peptide, MrVIB, has been
shown to have good selectivity for Nav1.8 channels (over other Na channels) and to inhibit
persistent inflammatory and neuropathic pain at
doses that do not have motor side effects.53 However, peptides are quickly catalyzed in vivo, and
more stable compounds need to be developed to
have better clinical efficacy.54 In addition, a recently described compound (A-803467) is selective for Nav1.8 and is effective in attenuating
inflammatory pain.55 It is likely that A-803467
has a largely peripheral site of action, as most
Nav1.8 channels are located on small-diameter
primary afferent neurons.39
Although VGSCs are essential for the generation and propagation of action potentials, they
do not act alone. Indeed, the 2 families of channels most involved in action potentials are the
VGSCs (discussed earlier) and voltage-gated K
channels. Voltage-gated K channels are involved
in action potential firing and frequency, membrane potential repolarization, regulation of resting membrane potential, and neurotransmitter release.56,57 In general terms, current flows into the
cell, through Na channels, on the rising phase of
the action potential, and out of the cell through
K channels during the action potential falling
phase.29 Therefore, it is the balance between the
current flow mediated by these families of channels that is a major contributor to the determination of neuronal excitability.
In a model of masseter inflammatory hyperalgesia, trigeminal neuronal excitability is associated with a decrease in voltage-gated K currents.58 Similar results are seen in CFA-induced
TMJ inflammatory hyperalgesia, where a significant decrease (approximately 50%) is reported
in transient voltage-gated K currents, and reduced threshold current is observed in trigeminal afferents innervating the TMJ12 and reflects
the corresponding decrease in Kv1.4 channel immunoreactivity.14 Recently, Yang et al59 showed
that neuron excitability and electrophysiological behavior are determined not only by the
intrinsic properties of membrane currents but
also by the balance between K currents that
are sensitive to the voltage-gated K channel
blocker 4-aminopyridine.

Neurobiology of Temporomandibular Joint Pain

There is a relative scarcity of clinically available antinociceptive drugs that act directly on
the K channels; however, many commonly
used analgesics, for example, those acting at
-opioid or -aminobutyric acid (GABA) receptors, partly act by potentiating a K conductance
via their respective G protein-coupled receptors.
Many other analgesic also act indirectly on K
reviewed by Ocaa et al.60 Taken together with
data presented in the previous section, enhanced neuronal excitability in inflammatory
hyperalgesia is mediated by both increases in the
Na conductance and decreases in the K conductance.

NMDA Receptors
Glutamate is the major neurotransmitter involved in fast excitatory synaptic transmission
and is released from presynaptic terminals to
bind to postsynaptic ionotropic (in the case of
fast transmission) or metabotropic receptors.61
There are 3 ionotropic glutamate receptors:
kainate, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and N-methyl-d-aspartate (NMDA).61 Of these, NMDA receptors have
received the most attention because of their
high Ca2 permeability and voltage sensitivity;
they are usually inactive at resting membrane
potential.62 NMDA receptors have been implicated in the mechanisms of many physiological
and pathological processes, including pain, ischemic stroke, and memory.61 Importantly, NMDA
receptors have been implicated in synaptic plasticity associated with pain for more than 20
years,63-65 and most of the research has focused
on NMDA receptors located on postsynaptic
neurons in the spinal cord or medullary dorsal
horn.23,66,67 In keeping with the theme of peripheral sensitization, we review the evidence for
NMDA receptors in primary afferent neurons, with
emphasis on those innervating the TMJ and masseter muscle. It is worth considering here that
inflammation causes increases in glutamate in the
knee joint, possibly release from peripheral primary afferent terminals,68 and is likely to do the
same in the TMJ. In addition, injection of glutamate into the masseter muscle of human subjects
evokes pain, and this response can be attenuated
with coinjection of NMDA receptor antagonists.69
Although it is clear that NMDA receptors on
second-order sensory neurons in the spinal cord

67

and medullary dorsal horn contribute to the

development and maintenance of inflammatoryinduced central sensitization,70-74 the role of
NMDA receptors in the development and maintenance of inflammatory-induced peripheral
sensitization is not well understood. Several reports have confirmed that peripheral NMDA receptors are located in the soma of sensory neurons in the DRG,75-79 peripheral nerves, and
terminals of primary afferent fibers that innervate skin and muscle.80-83 NMDA receptors are
composed of the NR1 and at least 1 of 4 NR2 (A,
B, C, and D) subunits, and are present in varying
degrees in different populations of DRG neurons,77 implying different functional roles for
some of the receptor subunits. Dong et al,84
reported that 20% and 31% of trigeminal ganglion neurons that innervate the masseter muscle of male rats express the NR2A and B subunits, respectively. Du et al85 and Carlton and
Coggeshall86 reported an upregulation of NR1
in peripheral axons after CFA-induced inflammation, whereas Wang et al79 reported a downregulation, predominantly in the soma of smalland medium-sized DRG neurons. Lee and Ro87
reported downregulation of the NR1, but not
NR2A or NR2B subunits, in trigeminal ganglion
neurons after inflammation of the masseter muscle. These findings are consistent with anterograde transport of NMDA receptors to peripheral nerve terminals85,87 after inflammation,
suggesting that peripheral NMDA receptors may
be involved in inflammatory-induced pain in
both the spinal and trigeminal system.
Peripheral injection of NMDA receptor antagonists reduces nociceptive behaviors in animals with inflammatory pain, implying that
NMDA receptors are indeed functional at the
periphery. For example, MK-801 (NMDA receptor antagonist) injection into the inflamed hind
paw returns mechanical sensitivity to normal (preinflammation) levels,85,88,89 as does application of
AP5 (a nonselective NMDA antagonist)88,90 and
the more specific NR2B antagonist CP-101,606.91
In the trigeminal system, it has been reported that
compared with injection of NMDA alone, coinjection of either ketamine (NMDA antagonist) or
ifenprodil (specific NR2B antagonist) significantly
attenuates NMDA-evoked masseter afferent fiber
discharge,84 and ketamine injected with glutamate
into the masseter muscle reduces glutamate-induced pain in humans,69 but neither of these stud-

68

Jennings et al

ies used inflammatory models. The importance of

NMDA antagonists in these NMDA- and glutamate-evoked pain models has been reviewed extensively.69,88,92,93
The development of clinically useful antinociceptive NMDA receptor antagonists has been
made difficult because NMDA receptors are
widely distributed within neuronal tissues,61 and
thus complete blockade of NMDA receptors has
wide-ranging and unacceptable side effects, such
as memory impairment and ataxia.94 Although
clinical trials have shown efficacy for systemically
administered NMDA antagonists in the perioperative period,95-97 such administration is limited to in-patients. However, more specific administration of NDMA receptor antagonists (for
example, into a joint capsule98) or the use of
NMDA receptor antagonists that do not penetrate the blood-brain barrier (or do so poorly)
has shown good efficacy in reducing neuropathic pain without marked side effects.94 The
effect of applying peripheral-acting NMDA antagonists directly into the inflamed human TMJ
has not yet been tested.

P2X Receptors
Purine receptors have been widely implicated in
pain processing since the 1970s when adenosine
5=tri-phosphate (ATP) was shown to induce pain
when applied to a blister base in human studies,99 causing an increase in sensory neuron firing.100 Since then, many further studies have
demonstrated purine receptor involvement in
pain.101-105 The purine receptors are of 2 types:
ionotropic (P2X) and metabotropic (P2Y), both
of which are stimulated by ATP. Seven P2X receptor subtypes have been cloned, and some
occur as heteromultimers (eg, P2X2/3, P2X1/5,
and P2X4/6 receptors). In the spinal somatosensory system, all P2X receptor subtypes with the
exception of P2X7 are expressed in spinal dorsal
horn neurons, DRG soma, and the central terminals of primary afferent neurons.106-108 P2X7
receptor subtype protein localization is controversial, as the antibodies still label something in
P2X7 knockout mice.109,110 P2X7 is, however,
expressed in glial cells, including microglia, astrocytes, and satellite glia cells, which have all
been implicated in pain conditions.111,112
P2X channels are permeable to Na and
2
Ca , with some members of the family mediat-

ing a Ca2 flux equal to that of NMDA receptors, previously considered to mediate the largest transmitter-gated channel Ca2 current.113
The members of the P2X family mediating the
smallest Ca2 flux are the homomeric P2X3 receptor and heteromeric P2X2/3 receptor; these
receptors mediate a Ca2 current of a similar
magnitude to TRPV1 receptors.113 P2X receptors are thus important in nociception, as Ca2
influx is thought to contribute to the induction
of chronic pain.23
In primary sensory neurons, much attention
has been focused on P2X3 receptors because
they are reported to be selectively and
uniquely expressed in a subset of predominantly small, presumed nociceptive DRG neurons, including both their central and peripheral terminals, but not in postsynaptic dorsal
horn neurons.102,108,114 In addition, activation
of P2X2/3 receptors on central terminals of primary afferent fibers results in large increases in
excitatory neurotransmission.115 P2X3 receptors
are reported to be predominantly associated
with nonpeptidergic spinal afferents that are
sensitive to capsaicin, bind isolectin B4 (IB4),
terminate in the inner part of dorsal horn lamina
II, and may be differentially involved, compared
with peptide-containing afferents, in certain pain
conditions (eg, inflammatory compared with
acute and neuropathic pain).116 However, the
neurochemical profiles of neurons that express
P2X3 appear to be quite different in trigeminal
sensory neurons. For example, although neurons containing P2X3 receptors show almost
complete colocalization with IB4 in DRG (98%99%),116,117 there is less colocalization in TG
neurons (64%-74%).117,118,119 In the TG, P2X3
receptors are also expressed on peptide-containing cells118 and myelinated medium-sized neurons (possibly A afferents).119
P2X3 receptors have further been reported
on trigeminal sensory neurons innervating the
TMJ120,121 and masseter muscle.118 In animal
models, inflammation of either the masseter muscle118 or TMJ121 results in both behavioral hypersensitivity and increases in P2X3 receptor immunoreactivity in the sensory neurons of the TG.
Administration of a P2X antagonist pyridoxalphosphate-6-azophenyl-2=,4=-disulfonic acid (PPADS)
significantly reduces hyperalgesia induced by TMJ
inflammation,121,122 as does the more specific P2X
antagonist 2=,3=-O-(2,4,6-trinitrophenyl) adeno-

Neurobiology of Temporomandibular Joint Pain

sine 5=-triphosphate.121 In addition, behavioral hyperalgesia could be induced by injecting a specific

P2X agonist into the TMJ.122 Further evidence that
P2X3 and P2X2/3 receptors are involved in inflammatory hyperalgesia is presented in studies on animals, where both P2X2 and P2X3 receptors have
been knocked out.123 These animals present
much-reduced inflammatory hyperalgesia compared with wild-type control animals.123
Given that P2X3 receptors are only located on a
subset of nociceptive neurons, they are an obvious
therapeutic target. The recent development of the
first non-nucleotide antagonist of P2X3 and
P2X2/3 receptors124 has exciting therapeutic implications, as it is both selective and potent for these
receptors in nociceptive pathways and has good
bioavailability. Initial preclinical studies have
shown that when administered peripherally,
A-317491 can attenuate inflammatory hyperalgesia.124-126 In addition, A-317491 is reported to
poorly penetrate the blood brain barrier,126 and
thus is likely to be a peripheral-acting analgesic.

Conclusions
We have reviewed several of the main ion channels
and receptors reported to be involved in primary
afferent hyperexcitability that accompanies inflammatory TMJ pain. The primary afferent neurons
that innervate the TMJ and the receptors and
channels mentioned in this review are actively being investigated as targets for the next generation
of peripherally acting drugs used in the treatment
of TMJ pain. The benefit of peripherally acting
drugs is that they have potentially fewer side effects
than drugs that penetrate the CNS. In addition, we
have provided evidence that some peripherally active, experimental compounds attenuate inflammatory pain in preclinical studies, and we expect
that these compounds or the like will be used
clinically in the coming years.

References
1. LeResche L: Epidemiology of temporomandibular disorders: Implications for the investigation of etiologic
factors. Crit Rev Oral Biol Med 8:291-305, 1997
2. Oral K, Bal Kucuk B, Ebeoglu B, et al: Etiology of
temporomandibular disorder pain. Agri 21:89-94, 2009
3. Dworkin SF, LeResche L: Research diagnostic criteria
for temporomandibular disorders: Review, criteria, examinations and specifications, critique. J Craniomandib Disord 6:301-55, 1992

69

4. Chang H, Israel H: Analysis of inflammatory mediators

in temporomandibular joint synovial fluid lavage samples of symptomatic patients and asymptomatic controls. J Oral Maxillofac Surg 63:761-5, 2005
5. Gynther GW, Dijkgraaf LC, Reinholt FP, et al: Synovial
inflammation in arthroscopically obtained biopsy specimens from the temporomandibular joint: A review of
the literature and a proposed histologic grading system.
J Oral Maxillofac Surg 56:1281-6, 1998
6. Sessle BJ, Hu JW: Mechanisms of pain arising from articular tissues. Can J Physiol Pharmacol 69:617-26, 1991
7. Svensson P, Graven-Nielsen T: Craniofacial muscle
pain: Review of mechanisms and clinical manifestations. J Orofac Pain 15:117-45, 2001
8. Barros VdeM, Seraidarian PI, Crtes MI, et al: The
impact of orofacial pain on the quality of life of patients
with temporomandibular disorder. J Orofac Pain 23:2837, 2009
9. John MT, Reissmann DR, Schierz O, et al: Oral healthrelated quality of life in patients with temporomandibular disorders. J Orofac Pain 21:46-54, 2007
10. Reissmann DR, John MT, Schierz O, et al: Functional
and psychosocial impact related to specific temporomandibular disorder diagnoses. J Dent 35:643-50, 2007
11. Takeda M, Tanimoto T, Ikeda M, et al: Temporomandibular joint inflammation potentiates the excitability
of trigeminal root ganglion neurons innervating the
facial skin in rats. J Neurophysiol 93:2723-38, 2005
12. Takeda M, Tanimoto T, Ikeda M, et al: Enhanced
excitability of rat trigeminal root ganglion neurons via
decrease in A-type potassium currents following temporomandibular joint inflammation. Neuroscience
138:621-30, 2006
13. Takeda M, Tanimoto T, Nasu M, et al: Activation of
NK1 receptor of trigeminal root ganglion via substance
P paracrine mechanism contributes to the mechanical
allodynia in the temporomandibular joint inflammation in rats. Pain 116:375-85, 2005
14. Takeda M, Tanimoto T, Nasu M, et al: Temporomandibular joint inflammation decreases the voltage-gated
K channel subtype 1.4-immunoreactivity of trigeminal ganglion neurons in rats. Eur J Pain 12:189-95, 2008
15. Ivanusic JJ, Beaini D, Hatch R, et al: N-methyl-d-aspartate receptors contribute to mechanical hypersensitivity
induced by injection of Complete Freunds Adjuvant
into the Temporomandibular joint of rats. Eur J Pain
15:179-185, 2011
16. Takeuchi Y, Zeredo JL, Fujiyama R, et al: Effects of
experimentally induced inflammation on temporomandibular joint nociceptors in rats. Neurosci Lett 354:
172-4, 2004
17. Kaczorowski GJ, McManus OB, Priest BT, et al: Ion
channels as drug targets: The next GPCRs. J Gen
Physiol 131:399-405, 2008
18. Sessle BJ: Orofacial pain, in Merskey H, Loeser JD,
Dubner R (eds): The Paths of Pain 1975-2005. Seattle,
WA, IASP, 2005, pp 131-150
19. Takeuchi Y, Toda K: Subtypes of nociceptive units in
the rat temporomandibular joint. Brain Res Bull 61:
603-8, 2003
20. Devor M: Unexplained peculiarities of the dorsal root
ganglion. Pain S27-S35, 1999

70

Jennings et al

21. Lawson SN, Waddell PJ: Soma neurofilament immunoreactivity is related to cell size and fibre conduction
velocity in rat primary sensory neurons. J Physiol 435:
41-63, 1991
22. Willis WD Jr, Coggeshall RE: Sensory receptors and
peripheral nerves, in Sensory Mechanisms of the Spinal
Cord. New York, NY, Kluwer Academic/Plenum Publishers, 2004
23. Woolf CJ, Salter MW: Neuronal plasticity: Increasing
the gain in pain. Science 288:1765-9, 2000
24. Maixner W, Fillingim R, Sigurdsson A, et al: Sensitivity
of patients with painful temporomandibular disorders
to experimentally evoked pain: Evidence for altered
temporal summation of pain. Pain 76:71-81, 1998
25. Wall PD: The prevention of postoperative pain. Pain
33:289-90, 1988
26. Thalakoti S, Patil VV, Damodaram S, et al: Neuron-glia
signaling in trigeminal ganglion: Implications for migraine pathology. Headache 47:1008-23, 2007
27. Woolf CJ, Ma Q: NociceptorsNoxious stimulus detectors. Neuron 55:353-64, 2007
28. Sisk AL: Long-acting local anesthetics in dentistry.
Anesth Prog 39:53-60, 1992
29. Bean BP: The action potential in mammalian central
neurons. Nat Rev Neurosci 8:451-65, 2007
30. Park CK, Kim K, Jung SJ, et al: Molecular mechanism
for local anesthetic action of eugenol in the rat trigeminal system. Pain 144:84-94, 2009
31. Chabal C, Jacobson L, Russell LC, et al: Pain response
to perineuromal injection of normal saline, epinephrine, and lidocaine in humans. Pain 49:9-12, 1992
32. Rizzo MA: Successful treatment of painful traumatic
mononeuropathy with carbamazepine: Insights into a
possible molecular pain mechanism. J Neurol Sci 152:
103-6, 1997
33. Morgan JR, Gebhart GF: Characterization of a model of
chronic orofacial hyperalgesia in the rat: Contribution
of NA(V) 1.8. J Pain 9:522-31, 2008
34. Roveroni RC, Parada CA, Ceclia M, et al: Development
of a behavioral model of TMJ pain in rats: The TMJ
formalin test. Pain 94:185-91, 2001
35. Lai J, Porreca F, Hunter JC, et al: Voltage-gated sodium
channels and hyperalgesia. Annu Rev Pharmacol Toxicol 44:371-97, 2004
36. Catterall WA: Structure and function of voltage-gated
ion channels. Trends Neurosci 16:500-6, 1993
37. Djouhri L, Newton R, Levinson SR, et al: Sensory and
electrophysiological properties of guinea-pig sensory
neurones expressing Nav1.7 (PN1) Na channel alpha
subunit protein. J Physiol 546:565-76, 2003
38. Djouhri L, Fang X, Okuse K, et al: The TTX-resistant
sodium channel Nav 1.8 (SNS/PN3): Expression and correlation with membrane properties in rat nociceptive primary afferent neurons. J Physiol 550:739-52, 2003
39. Akopian AN, Sivilotti L, Wood JN: A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature 379:257-62, 1996
40. Fang X, Djouhri L, Black JA, et al: The presence and
role of the tetrodotoxin-resistant sodium channel
Na(v) 1.9 (NaN) in nociceptive primary afferent neurons. J Neurosci 22:7425-33, 2002

41. Nassar MA, Stirling LC, Forlani G, et al: Nociceptorspecific gene deletion reveals a major role for Nav1.7
(PN1) in acute and inflammatory pain. Proc Natl Acad
Sci U S A 101:12706-11, 2004
42. Matthews EA, Wood JN, Dickenson AH: Na-v 1.8-null
mice show stimulus-dependent deficits in spinal neuronal activity. Mol Pain 2:5, 2006
43. Akopian AN, Souslova V, England S, et al: The tetrodotoxin-resistant sodium channel SNS has a specialized
function in pain pathways. Nat Neurosci 2:541-8, 1999
44. Amaya F, Wang H, Costigan M, et al: The voltage-gated
sodium channel Na(v)1.9 is an effector of peripheral
inflammatory pain hypersensitivity. J Neurosci 26:
12852-60, 2006
45. Waxman SG, Dib-Hajj S, Cummins TR, et al: Sodium
channels and pain. Proc Natl Acad Sci U S A 96:7635-9,
1999
46. Flake NM, Gold MS: Inflammation alters sodium currents and excitability of temporomandibular joint afferents. Neurosci Lett 384:294-9, 2005
47. England S, Bevan S, Docherty RJ, et al: PGE2 modulates
the tetrodotoxin-resistant sodium current in neonatal
rat dorsal root ganglion neurones via the cyclic AMPprotein kinase A cascade. J Physiol 495:429-40, 1996
48. Fitzgerald EM, Okuse K, Wood JN, et al: cAMP-dependent phosphorylation of the tetrodotoxin-resistant voltage-dependent sodium channel SNS. J Physiol 516:43346, 1999
49. Gold MS, Reichling DB, Shuster MJ, et al: Hyperalgesic
agents increase a tetrodotoxin-resistant Na current in
nociceptors. Proc Natl Acad Sci U S A 93:1108-12, 1996
50. Curley J, Castillo J, Hotz J, et al: Prolonged regional
nerve blockade. Injectable biodegradable bupivacaine/
polyester microspheres. Anesthesiology 84:1401-10,
1996
51. Binshtok AM, Bean BP, Woolf CJ: Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium
channel blockers. Nature 449:607-U613, 2007
52. Binshtok AM, Gerner P, Oh SB, et al: Coapplication of
lidocaine and the permanently charged sodium channel blocker QX-314 produces a long-lasting nociceptive
blockade in rodents. Anesthesiology 111:127-37, 2009
53. Ekberg J, Jayamanne A, Vaughan CW, et al: muOconotoxin MrVIB selectively blocks Nav1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits. Proc Natl Acad Sci U S A
103:17030-5, 2006
54. Terlau H, Olivera BM: Conus venoms: A rich source of
novel ion channel-targeted peptides. Physiol Rev 84:4168, 2004
55. Jarvis MF, Honore P, Shieh CC, et al: A-803467, a
potent and selective Nav1.8 sodium channel blocker,
attenuates neuropathic and inflammatory pain in the
rat. Proc Natl Acad Sci U S A 104:8520-5, 2007
56. Mathie A, Wooltorton JR, Watkins CS: Voltage-activated
potassium channels in mammalian neurons and their
block by novel pharmacological agents. Gen Pharmacol
30:13-24, 1998
57. Yellen G: The voltage-gated potassium channels and
their relatives. Nature 419:35-42, 2002

Neurobiology of Temporomandibular Joint Pain

58. Harriott AM, Dessem D, Gold MS: Inflammation increases the excitability of masseter muscle afferents.
Neuroscience 141:433-42, 2006
59. Yang J, Xing JL, Wu NP, et al: Membrane current-based
mechanisms for excitability transitions in neurons of
the rat mesencephalic trigeminal nuclei. Neuroscience
163:799-810, 2009
60. Ocaa M, Cendn CM, Cobos EJ, et al: Potassium channels and pain: Present realities and future opportunities. Eur J Pharmacol 500:203-19, 2004
61. Dingledine R, Borges K, Bowie D, et al: The glutamate
receptor ion channels. Pharmacol Rev 51:7-61, 1999
62. Cull-Candy S, Brickley S, Farrant M: NMDA receptor
subunits: Diversity, development and disease. Curr
Opin Neurobiol 11:327-35, 2001
63. Davies SN, Lodge D: Evidence for involvement of Nmethylaspartate receptors in wind-up of class 2 neurones in the dorsal horn of the rat. Brain Res 424:402-6,
1987
64. Dickenson AH, Sullivan AF: Evidence for a role of the
NMDA receptor in the frequency dependent potentiation of deep rat dorsal horn nociceptive neurones following C fibre stimulation. Neuropharmacology 26:
1235-8, 1987
65. Headley PM, Parsons CG, West DC: The role of Nmethylaspartate receptors in mediating responses of rat
and cat spinal neurones to defined sensory stimuli.
J Physiol 385:169-88, 1987
66. Salter MW: Cellular neuroplasticity mechanisms mediating pain persistence. J Orofac Pain 18:318-24,
2004
67. Sessle BJ: Acute and chronic craniofacial pain: Brainstem mechanisms of nociceptive transmission and neuroplasticity, and their clinical correlates. Crit Rev Oral
Biol Med 11:57-91, 2000
68. Lawand NB, McNearney T, Westlund KN: Amino acid
release into the knee joint: Key role in nociception and
inflammation. Pain 86:69-74, 2000
69. Cairns BE, Svensson P, Wang K, et al: Activation of
peripheral NMDA receptors contributes to human pain
and rat afferent discharges evoked by injection of glutamate into the masseter muscle. J Neurophysiol 90:
2098-105, 2003
70. Guo H, Huang LY: Alteration in the voltage dependence of NMDA receptor channels in rat dorsal horn
neurones following peripheral inflammation. J Physiol
537:115-23, 2001
71. Hama A, Woon Lee J, Sagen J: Differential efficacy of
intrathecal NMDA receptor antagonists on inflammatory mechanical and thermal hyperalgesia in rats. Eur
J Pharmacol 459:49-58, 2003
72. Herrero JF, Laird JM, Lpez-Garca JA: Wind-up of
spinal cord neurones and pain sensation: Much ado
about something? Prog Neurobiol 61:169-203, 2000
73. Ren K, Dubner R: NMDA receptor antagonists attenuate mechanical hyperalgesia in rats with unilateral inflammation of the hindpaw. Neurosci Lett 163:22-6,
1993
74. Spraggins DS, Turnbach ME, Randich A: Effects of
glutamate receptor antagonists on spinal dorsal horn
neurons during zymosan-induced inflammation in rats.
J Pain 2:12-24, 2001

71

75. Li J, McRoberts JA, Nie J, et al: Electrophysiological

characterization of N-methyl-d-aspartate receptors in
rat dorsal root ganglia neurons. Pain 109:443-52, 2004
76. Ma QP, Hargreaves RJ: Localization of N-methyl-D-aspartate NR2B subunits on primary sensory neurons that
give rise to small-caliber sciatic nerve fibers in rats.
Neuroscience 101:699-707, 2000
77. Marvizn JC, McRoberts JA, Ennes HS, et al: Two Nmethyl-D-aspartate receptors in rat dorsal root ganglia
with different subunit composition and localization.
J Comp Neurol 446:325-41, 2002
78. Sato K, Kiyama H, Park HT, et al: AMPA, KA and
NMDA receptors are expressed in the rat DRG neurones. Neuroreport 4:1263-5, 1993
79. Wang H, Zhang RX, Wang R, et al: Decreased expression of N-methyl-d-aspartate (NMDA) receptors in rat
dorsal root ganglion following complete Freunds adjuvant-induced inflammation: An immunocytochemical study for NMDA NR1 subunit. Neurosci Lett 265:
195-8, 1999
80. Alfredson H, Forsgren S, Thorsen K, et al: In vivo
microdialysis and immunohistochemical analyses of
tendon tissue demonstrated high amounts of free glutamate and glutamate NMDAR1 receptors, but no signs
of inflammation, in Jumpers knee. J Orthop Res 19:
881-6, 2001
81. Carlton SM, Hargett GL, Coggeshall RE: Localization
and activation of glutamate receptors in unmyelinated
axons of rat glabrous skin. Neurosci Lett 197:25-8, 1995
82. Kinkelin I, Brcker EB, Koltzenburg M, et al: Localization of ionotropic glutamate receptors in peripheral
axons of human skin. Neurosci Lett 283:149-52, 2000
83. Lai KO, Ip NY: Postsynaptic signaling of new players at
the neuromuscular junction. J Neurocytol 32:727-41,
2003
84. Dong XD, Mann MK, Kumar U, et al: Sex-related differences in NMDA-evoked rat masseter muscle afferent
discharge result from estrogen-mediated modulation of
peripheral NMDA receptor activity. Neuroscience 146:
822-32, 2007
85. Du J, Zhou S, Coggeshall RE, et al: N-methyl-d-aspartate-induced excitation and sensitization of normal and
inflamed nociceptors. Neuroscience 118:547-62, 2003
86. Carlton SM, Coggeshall RE: Inflammation-induced
changes in peripheral glutamate receptor populations.
Brain Res 820:63-70, 1999
87. Lee J, Ro JY: Differential regulation of glutamate receptors in trigeminal ganglia following masseter inflammation. Neurosci Lett 421:91-5, 2007
88. Lam DK, Sessle BJ, Cairns BE, et al: Peripheral NMDA
receptor modulation of jaw muscle electromyographic
activity induced by capsaicin injection into the temporomandibular joint of rats. Brain Res 1046:68-76,
2005
89. Leem JW, Hwang JH, Hwang SJ, et al: The role of
peripheral N-methyl-D-aspartate receptors in Freunds
complete adjuvant induced mechanical hyperalgesia in
rats. Neurosci Lett 297:155-8, 2001
90. Wang C, Wang Y, Zhao Z: Peripheral NMDA and nonNMDA receptors contribute to nociception: An electrophysiological study. Brain Res Bull 52:31-4, 2000

72

Jennings et al

91. Taniguchi K, Shinjo K, Mizutani M, et al: Antinociceptive activity of CP-101,606, an NMDA receptor NR2B
subunit antagonist. Br J Pharmacol 122:809-12, 1997
92. Cairns BE, Sessle BJ, Hu JW: Characteristics of glutamate-evoked temporomandibular joint afferent activity
in the rat. J Neurophysiol 85:2446-54, 2001
93. Lam DK, Sessle BJ, Cairns BE, et al: Neural mechanisms
of temporomandibular joint and masticatory muscle
pain: A possible role for peripheral glutamate receptor
mechanisms. Pain Res Manag 10:145-52, 2005
94. Parsons CG: NMDA receptors as targets for drug action
in neuropathic pain. Eur J Pharmacol 429:71-8, 2001
95. Muir KW: Glutamate-based therapeutic approaches:
Clinical trials with NMDA antagonists. Curr Opin Pharmacol 6:53-60, 2006
96. McCartney CJ, Sinha A, Katz J: A qualitative systematic
review of the role of N-methyl-d-aspartate receptor antagonists in preventive analgesia. Anesth Analg 98:
1385-400, 2004
97. Elia N, Tramr MR: Ketamine and postoperative
painA quantitative systematic review of randomised
trials. Pain 113:61-70, 2005
98. Lawand NB, Willis WD, Westlund KN: Excitatory amino
acid receptor involvement in peripheral nociceptive
transmission in rats. Eur J Pharmacol 324:169-77, 1997
99. Bleehen T, Keele CA: Observations on the algogenic
actions of adenosine compounds on the human blister
base preparation. Pain 3:367-77, 1977
100. Bleehen T: The effects of adenine nucleotides on cutaneous afferent nerve activity. Br J Pharmacol 62:
573-7, 1978
101. Ambalavanar R, Dessem D: Emerging peripheral receptor targets for deep-tissue craniofacial pain therapies. J
Dent Res 88:201-11, 2009
102. Burnstock G: Purinergic P2 receptors as targets for
novel analgesics. Pharmacol Ther 110:433-54, 2006
103. Liu XJ, Salter MW: Purines and pain mechanisms: Recent developments. Curr Opin Investig Drugs 6:65-75,
2005
104. North RA: P2X3 receptors and peripheral pain mechanisms. J Physiol 554:301-8, 2004
105. Jennings EA, Cho H-j: Peripheral sensitization in migraine-role for P2X purinergic receptors in the duravascular sensory pathway. Drug Dev Res 68:321-8, 2007
106. Burnstock G: P2X receptors in sensory neurones. Br J
Anaesth 84:476-88, 2000
107. Khakh BS: Molecular physiology of P2X receptors and
ATP signalling at synapses. Nat Rev Neurosci 2:165-74,
2001
108. North RA: Molecular physiology of P2X receptors.
Physiol Rev 82:1013-67, 2002
109. Anderson CM, Nedergaard M: Emerging challenges of
assigning P2X7 receptor function and immunoreactivity in neurons. Trends Neurosci 29:257-62, 2006
110. Sim JA, Young MT, Sung HY, et al: Reanalysis of P2X7
receptor expression in rodent brain. J Neurosci 24:
6307-14, 2004
111. Hansson E: Could chronic pain and spread of pain
sensation be induced and maintained by glial activation? Acta Physiol 187:321-27, 2006

112. McGaraughty S, Chu KL, Namovic MT, et al: P2X7related modulation of pathological nociception in rats.
Neuroscience 146:1817-28, 2007
113. Egan TM, Khakh BS: Contribution of calcium ions to
P2X channel responses. J Neurosci 24:3413-20, 2004
114. Chen CC, Akopian AN, Sivilotti L, et al: A P2X purinoceptor expressed by a subset of sensory neurons. Nature 377:428-31, 1995
115. Jennings EA, Christie MJ, Sessle BJ: ATP potentiates
neurotransmission in the rat trigeminal subnucleus
caudalis. Neuroreport 17:1507-10, 2006
116. Bradbury EJ, Burnstock G, McMahon SB: The expression of P2X3 purinoreceptors in sensory neurons: Effects of axotomy and glial-derived neurotrophic factor.
Mol Cell Neurosci 12:256-68, 1998
117. Ruan HZ, Moules E, Burnstock G: Changes in P2X3
purinoceptors in sensory ganglia of the mouse during
embryonic and postnatal development. Histochem Cell
Biol 122:539-51, 2004
118. Ambalavanar R, Moritani M, Dessem D: Trigeminal
P2X3 receptor expression differs from dorsal root ganglion and is modulated by deep tissue inflammation.
Pain 117:280-91, 2005
119. Staikopoulos V, Sessle BJ, Furness JB, et al: Localization
of P2X2 and P2X3 receptors in rat trigeminal ganglion
neurons. Neuroscience 144:208-16, 2007
120. Ichikawa H, Fukunaga T, Jin HW, et al: VR1-, VRL-1and P2X3 receptor-immunoreactive innervation of the
rat temporomandibular joint. Brain Res 1008:131-6,
2004
121. Shinoda M, Ozaki N, Asai H, et al: Changes in P2X3
receptor expression in the trigeminal ganglion following monoarthritis of the temporomandibular joint in
rats. Pain 116:42-51, 2005
122. Oliveira MC, Parada CA, Veiga MC, et al: Evidence for
the involvement of endogenous ATP and P2X receptors in TMJ pain. Eur J Pain 9:87-93, 2005
123. Cockayne DA, Dunn PM, Zhong Y, et al: P2X2 knockout mice and P2X2/P2X3 double knockout mice reveal
a role for the P2X2 receptor subunit in mediating
multiple sensory effects of ATP. J Physiol 567:621-39,
2005
124. Jarvis MF, Burgard EC, McGaraughty S, et al: A-317491,
a novel potent and selective non-nucleotide antagonist
of P2X3 and P2X2/3 receptors, reduces chronic inflammatory and neuropathic pain in the rat. Proc Natl
Acad Sci U S A 99:17179-84, 2002
125. McGaraughty S, Wismer CT, Zhu CZ, et al: Effects of
A-317491, a novel and selective P2X(3)/P2X(2/3) receptor antagonist, on neuropathic, inflammatory and
chemogenic nociception following intrathecal and intraplantar administration. Br J Pharmacol 140: 1381-88,
2003
126. Wu G, Whiteside GT, Lee G, et al: A-317491, a selective
P2X(3)/P2X(2/3) receptor antagonist, reverses inflammatory mechanical hyperalgesia through action at
peripheral receptors in rats. Eur J Pharmacol 504:4553, 2004