Group Title: Molecular Pain 2005, 1:30
Title: Role of spinal cord glutamate transporter during normal sensory transmission and pathological pain states
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Title: Role of spinal cord glutamate transporter during normal sensory transmission and pathological pain states
Series Title: Molecular Pain 2005, 1:30
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Creator: Tao YX
Gu J
Stephens RL
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Molecular Pain

BioMed Central


Role of spinal cord glutamate transporter during normal sensory
transmission and pathological pain states
Yuan-Xiang Tao*1, Jianguo Gu2 and Robert L Stephens Jr3

Address: 'Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 355 Ross, 720 Rutland Ave.,
Baltimore, Maryland 21205, USA, 2Department of Oral and Maxillofacial Surgery, Mcknight Brain Institute and College of Dentistry, University
of Florida, Gainesville, Florida, 32610, USA and 3Department of Physiology and Cell Biology, The Ohio State University College of Medicine,
Columbus, Ohio 43210, USA
Email: Yuan-Xiang Tao*; Jianguo Gu; Robert L Stephens
* Corresponding author

Published: 21 October 2005
Molecular Pain 2005, 1:30 doi:10.1 186/1744-8069-1-30

Received: 22 August 2005
Accepted: 21 October 2005

This article is available from:
2005 Tao et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Glutamate is a neurotransmitter critical for spinal excitatory synaptic transmission and for
generation and maintenance of spinal states of pain hypersensitivity via activation of glutamate
receptors. Understanding the regulation of synaptically and non-synaptically released glutamate
associated with pathological pain is important in exploring novel molecular mechanisms and
developing therapeutic strategies of pathological pain. The glutamate transporter system is the
primary mechanism for the inactivation of synaptically released glutamate and the maintenance of
glutamate homeostasis. Recent studies demonstrated that spinal glutamate transporter inhibition
relieved pathological pain, suggesting that the spinal glutamate transporter might serve as a
therapeutic target for treatment of pathological pain. However, the exact function of glutamate
transporter in pathological pain is not completely understood. This report will review the evidence
for the role of the spinal glutamate transporter during normal sensory transmission and
pathological pain conditions and discuss potential mechanisms by which spinal glutamate
transporter is involved in pathological pain.

In addition to its essential metabolic role, glutamate is a
major mediator of excitatory signals in the central nervous
system and is involved in many physiologic and patho-
logic processes, such as excitatory synaptic transmission,
synaptic plasticity, cell death, stroke, and chronic pain
[1,2]. Glutamate exerts its signaling role by acting on
glutamate receptors, including N-methyl-D-aspartate
(NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazolepro-
pionic acid (AMPA)/kainate, and metabotropic glutamate
receptors. These receptors are located on the pre- and
post-synaptic membranes, as well as, at extra-synaptic
sites. Glutamate concentration in the synaptic cleft deter-
mines the extents of receptor stimulation and excitatory

synaptic transmission. It is of critical importance that the
extracellular glutamate concentration be kept at physio-
logical levels, as excessive activation of glutamate recep-
tors can lead to excitotoxicity and neuronal death [3]. The
clearance of glutamate from the synaptic cleft is princi-
pally dependent on Na+-dependent, high-affinity, neuro-
nal glutamate transporters present presynaptically,
postsynaptically, and perisynaptically, and on glial gluta-
mate transporters (Fig. 1). Currently, five isoforms of
glutamate transporters have been identified [3]: namely,
GLAST (glutamate/aspartate transporter), GLT-1 (gluta-
mate transporter-1), EAAC (excitatory amino acid carrier)
1, EAAT (excitatory amino-acid transporter) 4, and

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Nerve terminal

Figure I
Glutamate (Glu) uptake and Glu/glutamine (Gin) cycle. Glu
released from the nerve terminal by exocytosis is taken up
by neuronal Glu transporter present presynaptically (I) and
postsynaptically (2) and by glial Glu transporter (3). Glu/GIn
cycle is one type of Glu recycling, but the significance is still
unclear in vivo (see references 37 and 38). Astroglia detoxifies
Glu by converting it to Gin. Glu is subsequently released
from the glial cells by glial Gin transporter (4) and taken up
by neuronal Gin transporter (5). Neurons convert Gin back
to Glu, which is loaded into synaptic vesicles by vesicular Glu
transporter (6). 7: postsynaptic Glu receptors.

EAAT5. The human homologues of the three more ubiq-
uitous subtypes (GLAST, GLT-1, and EAAC1) are named
EAAT1, EAAT2, and EAAT3, respectively. The five isoforms
belong to the same gene-family and share 50-60% amino
acid sequence identity [3]. However, they have discrete
cellular and regional localizations. GLAST is present in
glial cells throughout the central nervous system, with
strong labeling in cerebellar Bergmann glia and more dif-
fuse labeling in the forebrain [3]. It is also transiently
expressed in a small number of neurons [4]. GLT-1 is
almost exclusively expressed on glia and is widespread
and abundant throughout the forebrain, cerebellum, and
spinal cord [4]. In contrast, EAAC1 is found predomi-
nantly in neurons of the spinal cord and brain [4,5].
EAAT4 has properties of a ligand-gated Cl-channel and is
localized mainly in cerebellar Purkinje cells [6]. EAAT5 is
retina-specific [7].

Given the well-documented evidence that glutamate acts
as a major excitatory neurotransmitter in primary afferent
terminals [2], it is expected that glutamate transporter
might be involved in excitatory sensory transmission and
pathological pain. Indeed, recent studies have revealed
that inhibition of spinal glutamate transporter produced
pro-nociceptive effects under normal conditions [8] and
have unexpected antinociceptive effects under pathologi-
cal pain conditions [9-11]. It is not completely under-

stood why the effects of spinal glutamate transporter
inhibition under pathological pain conditions are oppo-
site to its effects under normal conditions. In this review,
we will illustrate the expression and distribution of the
glutamate transporter in two major pain-related regions:
spinal cord and dorsal root ganglion (DRG). We will also
review the evidence for the role of the glutamate trans-
porter during normal sensory transmission and patholog-
ical pain conditions and discuss potential mechanisms by
which glutamate transporter is involved in pathological

Expression and distribution of glutamate
transporter in the spinal cord and dorsal root
In the spinal cord, three isoforms of glutamate transporter
(GLAST, GLT-1, and EAAC1) have been reported [4,12].
They are expressed in highest density within the superfi-
cial dorsal horn of the spinal cords of rats and mice (Fig.
2). GLT-1 and GLAST are exclusively distributed in glial
cells at perisynaptic sites in the superficial dorsal horn
[13]. EAAC1, in addition to its expression in the spinal
cord neurons, is detected in the DRG and distributed pre-
dominantly in the small DRG neurons (but not in DRG
glial cells) [12] (Fig. 3). Some of these EAAC1-positive
DRG neurons are positive for calcitonin gene-related pep-
tide (CGRP) or are labeled by IB4 [12,13]. Unilateral dor-
sal root rhizotomy shows less intense EAAC1
immunoreactivity in the superficial dorsal horn on the
ipsilateral side, compared to the contralateral side [12].
Moreover, confocal microscopy demonstrates that some
EAAC1-positive, small dot- or patch-like structures in the
superficial laminae are labeled by IB4 or are positive for
CGRP [12]. Under electron microscope, EAAC1 is associ-
ated with the axon terminal and dendritic membranes at
synaptic and non-synaptic sites and is present with CGRP
in the axons and the terminals in the superficial dorsal
horn [13]. The expression level and distribution pattern of
neuronal and glial glutamate transporters in the superfi-
cial dorsal horn suggest an important role for spinal gluta-
mate transporter in spinal nociceptive transmission. In
addition, the unique expression of EAAC1 in the small
DRG neurons and nociceptive primary afferent terminals
suggests that EAAC1 might have a distinct role in pain
processing, compared to GLT-1 and GLAST.

Role of the spinal cord glutamate transporter in
normal sensory transmission
Recently evidence suggests that spinal glutamate trans-
porter might play an important role in normal sensory
transmission. Liaw et al. [8] reported that intrathecal
injection of glutamate transporter blockers DL-threo-3-
benzyloxyaspartate (TBOA) and dihydrokainate (DHK)
produced significant and dose-dependent spontaneous
nociceptive behaviors, such as licking, shaking, and cau-

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Molecular Pain 2005, 1:30

Figure 2
Expression and distribution of the glutamate transporter in the dorsal root ganglion (A) and the spinal cord (B-D). EAAC I is
expressed mainly in small dorsal root ganglion cells (A) and distributed predominantly in the superficial dorsal horn of the spi-
nal cord (B). GLAST (C) and GLT- I (D) are expressed highly in the superficial dorsal horn and the region around the central
canal. Scale bars: 10 pm in A and 125 pm in B, C, and D.

dally directed biting, phenomena similar to the behaviors
caused by intrathecal glutamate receptor agonists, such as
glutamate, NMDA, or AMPA, when given intrathecally
[14-16]. Intrathecal TBOA also led to remarkable hyper-
sensitivity in response to thermal and mechanical stimuli
[8]. These findings are consistent with a previous report
that showed an increase in spontaneous activity and
responses of wide dynamic range neurons to both innoc-
uous mechanical (brush, pressure) and noxious mechani-
cal (pinch) stimuli after topical application of L-trans-
pyrrolidine-2,4-dicarboxylic acid (PDC), a glutamate
transporter blocker [17,18]. TBOA-induced behavioral
responses could be significantly blocked by intrathecal
injection of the NMDA receptor antagonists MK-801 and
AP-5, the non-NMDA receptor antagonist CNQX or the

nitric oxide synthase inhibitor L-NAME [8]. The effects of
DHK and PDC were thought to be partially due to their
non-specific interactions with glutamate receptors. How-
ever, unlike DHK and PDC, TBOA does not act as an ago-
nist or antagonist at glutamate receptors [9,19,20]. Thus,
spontaneous pain-related behaviors and sensory hyper-
sensitivity evoked by TBOA directly support the involve-
ment of glutamate transporter in normal excitatory
synaptic transmission in the spinal cord. In vivo microdi-
alysis analysis showed that intrathecal injection of TBOA
produced short-term elevation of extracellular glutamate
concentration in the spinal cord [8]. Topical application
of TBOA on the dorsal surface of the spinal cord also
resulted in a significant elevation of extracellular gluta-
mate concentrations demonstrated by in vivo glutamate

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Molecular Pain 2005, 1:30

Figure 3
Double-immunofluorescence histochemistry for EAAC I (A) and NeuN (B, a marker for neuronal nuclei), and their overlapping
(C) in the dorsal root ganglion. Scale bar: 10 pim.

voltametry [8]. These findings indicate that a decrease of
spinal glutamate uptake can lead to excessive glutamate
accumulation in the spinal cord, which might, in turn,
result in over-activation of glutamate receptors, and pro-
duction of spontaneous nociceptive behaviors and sen-
sory hypersensitivity. Thus, glutamate uptake through
spinal glutamate transporters is critical for maintaining
normal sensory transmission under physiological condi-

Expression and function of the spinal cord
glutamate transporter in pathological pain
Glutamate uptake and expression of glutamate transport-
ers in the spinal cord have been found to be changed
under pathological conditions associated with chronic
pain status. Chronic constriction nerve injury upregulated
glutamate transporter expression at day 1 and 4 postoper-
atively, but it downregulated glutamate transporter
expression at days 7 and 14 postoperatively [21]. Moreo-
ver, chronic constriction nerve injury significantly reduced
spinal glutamate uptake activity at day 5 postoperatively
[21]. Recently, another study showed that spinal nerve
ligation also markedly reduced glutamate uptake activity,
as demonstrated in spinal deep dorsal and ventral horn 4-
6 weeks after the nerve ligation [22]. Although the under-
lying mechanism by which neuropathic inputs cause the
decrease in spinal glutamate uptake is unclear, it is
thought that this decrease might contribute to the central
mechanisms of the development and maintenance of
pathological pain[21,22].

As shown above, inhibition of glutamate uptake produces
pronociceptive effects in normal animals [8]. Unexpect-
edly, in pathological pain states, inhibition of glutamate
transporter activity produced antinociceptive effects. For
example, glutamate transporter inhibitors attenuated the
induction of allodynia induced by PGE2, PGF,,, and
NMDA [9]. Inhibition or transient knockdown of spinal
GLT-1 led to a significant reduction of nociceptive behav-
ior in the formalin model [10]. Consistent with these
findings, the preliminary work from Yuan-Xiang Tao's
laboratory showed that three different glutamate trans-
porter inhibitors (TBOA, DHK, threo-3-hydroxyaspartate)
reduced formalin-induced nociceptive responses and
Complete Freund's adjuvant (CFA)-evoked thermal
hyperalgesia [11]. On the other hand, the glutamate trans-
porter activator MS-153, which is reported to accelerate
glutamate uptake in in vivo and in vitro studies [23-26],
had no effect in formalin tests when MS-153 was applied
via intrathecal injection, even at the highest dose (1,000
Gg/10 gl) [11]. Interestingly, Sung et al. reported that rilu-
zole, a glutamate transporter regulator, significantly atten-
uated thermal hyperalgesia and mechanical allodynia
after chronic constriction nerve injury [21], but this drug
was ineffective against peripheral neuropathic pain in a
clinical setting [27]. The reason for the discrepancy
between the two studies is unclear, but it is worth noting
that, in addition to increasing glutamate uptake, riluzole
has multiple actions on many systems [neuroprotective,
anticonvulsant, anxiolytic, and anesthetic qualities by its
blockade of sodium channel a-subunits, glutamate recep-
tors, and y-aminobutyric acid (GABA) reuptake and its sta-

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Molecular Pain 2005, 1:30

bilization of voltage-gated ion channels] [28-31]. Thus,
more selective drugs that promote spinal glutamate trans-
porter function are needed to demonstrate whether gluta-
mate transporter activators have possible efficacy in the
treatment of chronic pain.

The intriguing question remains as to why glutamate
transporter inhibitors have antinociceptive effects under
pathologic pain conditions that are opposite to their pro-
nociceptive effects under normal conditions. Several
mechanisms potentially contribute to the role of the
glutamate transporter inhibitors under pathological pain
states (Fig. 4). First, the blockade of spinal glutamate
transporter uptake inhibits clearance of glutamate, lead-
ing to the chronic elevation of spinal extracellular gluta-
mate, possibly subsequently causing excitotoxicity,
compromising or destroying subsceptible dorsal horn
neurons, and interfering with the transmission of pain sig-
naling. However, preliminary data from Dr. Tao's labora-
tory showed that transient glutamate transporter
inhibition did not produce significant spinal neuronal
damage in rat formalin or CFA model [11]. Second,
GABA, an inhibitory transmitter, is synthesized from
glutamate by glutamic acid decarboxylase. Do the
increased glutamate levels caused by glutamate trans-
porter inhibition lead to increased GABA in the spinal
cord? Recent work showed that inhibition of glutamate
transporter activity depleted both glutamate and GABA
neurotransmitter pools and reduced inhibitory postsyn-
aptic current (IPSC) and miniature IPSC amplitudes
[32,33]. Thus, if this property extends to the spinal cord,
one would expect that blockade of spinal glutamate trans-
porter would decrease the amount of GABA in GABAergic
terminals and reduce IPSP or IPSC. This expectation
would not explain the mechanisms of antinociception by
glutamate transporter blocker in pathological pain. Third,
inhibition ofreuptake through presynaptic EAAC1 and/or
the glutamate/glutamine cycle in the spinal cord might
result in a depletion of glutamate in synaptic vesicles and
a decrease in presynaptically released glutamate, leading
to a reduction in glutamate receptor-mediated nociceptive
transmission. It is documented that abundant glutamate
is distributed in intracellular space, particularly inside
nerve terminals [3,34,35]. As a precursor for transmitter
glutamate, glutamine is also rich in the intracellular and
extracellular fluid [3]. Moreover, although it has been
demonstrated in vitro that glutamine is a precursor of
transmitter glutamate, the in vivo evidence regarding the
glutamate/glutamine cycle is less convincing [36]. The
ability of glutamatergic neurons to sustain release of
glutamate independently of glutamine might be related to
a newly found capacity for pyruvate carboxylation
[37,38]. Pyruvate carboxylation replenishes the loss of a-
ketoglutarare from the tricarboxylic acid cycle that is
inherent in release of glutamate. Thus, inhibition of spi-

nal glutamate transporter might not cause the depletion
of glutamate in presynaptic vesicles in pathological pain.
Fourth, chronic elevation of extracellular glutamate
caused by glutamate uptake inhibition might activate the
inhibitory presynaptic metabotropic glutamate receptors
(mGluRs) [39-41] and promote a postsynaptic desensiti-
zation of glutamate receptors [40]. It is possible that, dur-
ing pathological pain conditions, glutamate transporter
inhibitor-produced antinociception might be due to the
decreased release of pre-synaptic glutamate via activation
of inhibitory mGluRs in primary afferent terminals and/or
reduced postsynaptic efficacy of glutamate via desensitiza-
tion of glutamate receptors in the spinal dorsal horn neu-
rons. Finally, glutamate transporter inhibitors might
produce antinociception in pathological pain by the
mechanism of blocking inverse operation of the gluta-
mate transporter. It is well documented that the glutamate
transporter imports one glutamate ion and co-transports
three Na+ ions into the cell [42] and that transporter func-
tion is dependent upon both the membrane potential and
the transmembrane ion gradients established by Na+-
K+ATPase as driving forces [43,44]. Under physiological
conditions, these forces are sufficient to maintain the con-
centration gradient of micromolar extracellular glutamate
against millimolar intracellular glutamate through gluta-
mate transporter uptake [3,42]. However, under patho-
logical conditions, metabolic insults that deplete
intracellular energy and alter ionic gradients can lead to
reversed action of the glutamate transporter [3]. For exam-
ple, during brain ischemia, ATP is depleted and impair-
ment of Na+-K+ATPase results in the increases in
intracellular Na+ ions and extracellular K+ ions, which
causes inverse operation of the glutamate transporter and
release of glutamate into the extracellular space [3].
Indeed, the glutamate transporter inhibitors (e.g., TBOA)
reduce glutamate release and have neuroprotective
actions in brain ischemia [20]. Does pathological persist-
ent pain cause cellular energy insufficiency that inverses
the glutamate transporter operation to release glutamate
in the spinal cord? Metabolic activity and energy demand
significantly increase in the spinal cord under pathologi-
cal pain conditions [45-48]. Such hyperactive states of spi-
nal neuronal and glial cell activities might not only
consume large amounts of cell energy, but also disturb
energy metabolism, decrease ATP, and result in energy
insufficiency that might reverse spinal glutamate trans-
porter operation to release glutamate. It is possible that
blocking the reversed glutamate transporter-mediated
glutamate release is an underlying mechanism of antino-
ciception produced by glutamate transporter inhibition
under chronic pain conditions.

Taken together, it is evident that at least five potential
mechanisms are involved in the action of glutamate trans-
porter inhibitors during pathological pain (Fig. 4). In the

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Molecular Pain 2005, 1:30

Pathological Pain

Energy insufficiency

Glu uptake 1

Inverse operation of Glu transporter

Extracellular Glu T'

I (-) Glu tra

Extracellular Glu t '

^\\ \


< ^od

Glu release 1'


Extracellular Glu (-
Extracellular Glu ,

Reuptake and/or
Glu/Gln recycle 11


Glu depletion in
synaptic vesicles

Figure 4
Two distinct models for the role of glutamate (Glu) transporter inhibitors in pathological pain. Pathological pain might cause
Glu uptake decrease and energy insufficiency in the spinal cord. The latter may, in turn, results in Glu uptake decrease as well
as inverse operation of spinal Glu transporter to release Glu. In one model, Glu transporter inhibitors further block Glu
uptake and enhance the increase in extracellular Glu levels, perhaps leading to dorsal horn neuronal death, increase of spinal
GABA contents, activation of inhibitory presynaptic mGluRs, and desensitization of postsynaptic Glu receptors. Glu trans-
porter inhibitors also block neuronal Glu transporter reuptake and/or the Glu/GIn cycle via inhibition of glial Glu transporter,
resulting in Glu depletion of synaptic vesicles in primary afferent terminals. In contrast, Glu transporter inhibitors block inverse
operation of Glu transporter to release Glu and decrease extracellular Glu levels in another model.

first four mechanisms, glutamate transporter inhibitors
lead to an increase in spinal extracellular glutamate levels,
whereas, in the last one, glutamate transporter inhibitors
block the reversed glutamate transporter-mediated gluta-

mate release, and reduce extracellular glutamate levels
(Fig. 4). Therefore, two distinct models explain the role of
spinal glutamate transporter in pathological pain (Fig. 4).
Determining extracellular glutamate levels in the spinal

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Molecular Pain 2005, 1:30


cord following glutamate transporter inhibition during
pathological pain might be a key to determine the mech-
anisms of glutamate transporter inhibitor-produced anti-
nociception in the state of pathological pain.

Pathological pain, particularly as a result of nerve injury,
is poorly managed by current drugs, such as opioids and
non-steroidal anti-inflammatory drugs. Glutamate recep-
tor antagonists are effective in reducing pain hypersensi-
tivity in animal models and clinical settings, but with
unacceptable side effects. Glutamate transporter inhibi-
tors have recently been shown to produce antinociceptive
effects in several preclinical pathological pain models.
Further studies to delineate the role of the spinal gluta-
mate transporters during chronic pain states might lead to
better strategies for the prevention and therapy of chronic

This work was supported by the Johns Hopkins University Blaustein Pain
Research Fund and in part by NIH grant NS44219. The corresponding
author would like to thank Drs. John A. Ulatowski and Roger A. Johns for
their support. The authors thank Tzipora Sofare, MA, for her editorial

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