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Role of spinal cord glutamate transporter during normal sensory transmission and pathological pain states
© Tao et al; licensee BioMed Central Ltd. 2005
Received: 22 August 2005
Accepted: 21 October 2005
Published: 21 October 2005
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.
Given the well-documented evidence that glutamate acts as a major excitatory neurotransmitter in primary afferent terminals , 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  and have unexpected antinociceptive effects under pathological pain conditions [9–11]. It is not completely understood why the effects of spinal glutamate transporter inhibition under pathological pain conditions are opposite 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 transporter during normal sensory transmission and pathological pain conditions and discuss potential mechanisms by which glutamate transporter is involved in pathological pain.
Expression and distribution of glutamate transporter in the spinal cord and dorsal root ganglion
Role of the spinal cord glutamate transporter in normal sensory transmission
Recently evidence suggests that spinal glutamate transporter might play an important role in normal sensory transmission. Liaw et al.  reported that intrathecal injection of glutamate transporter blockers DL-threo-β-benzyloxyaspartate (TBOA) and dihydrokainate (DHK) produced significant and dose-dependent spontaneous nociceptive behaviors, such as licking, shaking, and caudally 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 hypersensitivity in response to thermal and mechanical stimuli . These findings are consistent with a previous report that showed an increase in spontaneous activity and responses of wide dynamic range neurons to both innocuous mechanical (brush, pressure) and noxious mechanical (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 . The effects of DHK and PDC were thought to be partially due to their non-specific interactions with glutamate receptors. However, unlike DHK and PDC, TBOA does not act as an agonist or antagonist at glutamate receptors [9, 19, 20]. Thus, spontaneous pain-related behaviors and sensory hypersensitivity evoked by TBOA directly support the involvement of glutamate transporter in normal excitatory synaptic transmission in the spinal cord. In vivo microdialysis analysis showed that intrathecal injection of TBOA produced short-term elevation of extracellular glutamate concentration in the spinal cord . Topical application of TBOA on the dorsal surface of the spinal cord also resulted in a significant elevation of extracellular glutamate concentrations demonstrated by in vivo glutamate voltametry . 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 production of spontaneous nociceptive behaviors and sensory hypersensitivity. Thus, glutamate uptake through spinal glutamate transporters is critical for maintaining normal sensory transmission under physiological conditions.
Expression and function of the spinal cord glutamate transporter in pathological pain states
Glutamate uptake and expression of glutamate transporters 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 postoperatively, but it downregulated glutamate transporter expression at days 7 and 14 postoperatively . Moreover, chronic constriction nerve injury significantly reduced spinal glutamate uptake activity at day 5 postoperatively . 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 . Although the underlying 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 . Unexpectedly, 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, PGF2α, and NMDA . Inhibition or transient knockdown of spinal GLT-1 led to a significant reduction of nociceptive behavior in the formalin model . Consistent with these findings, the preliminary work from Yuan-Xiang Tao's laboratory showed that three different glutamate transporter inhibitors (TBOA, DHK, threo-3-hydroxyaspartate) reduced formalin-induced nociceptive responses and Complete Freund's adjuvant (CFA)-evoked thermal hyperalgesia . On the other hand, the glutamate transporter 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 μg/10 μl) . Interestingly, Sung et al. reported that riluzole, a glutamate transporter regulator, significantly attenuated thermal hyperalgesia and mechanical allodynia after chronic constriction nerve injury , but this drug was ineffective against peripheral neuropathic pain in a clinical setting . 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 α-subunits, glutamate receptors, and γ-aminobutyric acid (GABA) reuptake and its stabilization of voltage-gated ion channels] [28–31]. Thus, more selective drugs that promote spinal glutamate transporter function are needed to demonstrate whether glutamate transporter activators have possible efficacy in the treatment of chronic pain.
Taken together, it is evident that at least five potential mechanisms are involved in the action of glutamate transporter inhibitors during pathological pain (Fig. 4). In the 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 glutamate 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 cord following glutamate transporter inhibition during pathological pain might be a key to determine the mechanisms of glutamate transporter inhibitor-produced antinociception 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 receptor antagonists are effective in reducing pain hypersensitivity in animal models and clinical settings, but with unacceptable side effects. Glutamate transporter inhibitors have recently been shown to produce antinociceptive effects in several preclinical pathological pain models. Further studies to delineate the role of the spinal glutamate transporters during chronic pain states might lead to better strategies for the prevention and therapy of chronic pain.
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 assistance.
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