Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord

Wen Jinn Liaw; Robert L. Stephens; Brian C. Binns; Yachun Chu; Jehuda P. Sepkuty; Roger A. Johns; Jeffery D. Rothstein; Yuan Xiang Tao

doi:10.1016/j.pain.2005.02.006

Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord

Wen Jinn Liaw, Robert L. Stephens, Brian C. Binns, Yachun Chu, Jehuda P. Sepkuty, Roger A. Johns, Jeffery D. Rothstein, Yuan Xiang Tao

School of Medicine

Research output: Contribution to journal › Article › peer-review

117 Scopus citations

Abstract

Glutamate is a major excitatory neurotransmitter in primary afferent terminals and is critical for normal spinal excitatory synaptic transmission. However, little is known about the regulation of synaptically released glutamate in the spinal cord under physiologic conditions. The sodium-dependent, high-affinity glutamate transporters are the primary mechanism for the clearance of synaptically released glutamate. In the present study, we found that intrathecal injection of glutamate transporter blockers dl-threo-β- benzyloxyaspartate (TBOA) and dihydrokainate 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. Intrathecal TBOA also led to remarkable hypersensitivity in response to thermal and mechanical stimuli. These 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. In vivo microdialysis analysis showed short-term elevation of extracellular glutamate concentration in the spinal cord after intrathecal injection of TBOA. Furthermore, topical application of TBOA on the dorsal surface of the spinal cord resulted in a significant elevation of extracellular glutamate concentration demonstrated by in vivo glutamate voltametry. The present study indicates that defective spinal glutamate uptake caused by inhibition of glutamate transporters leads to excessive glutamate accumulation in the spinal cord. The latter results in persistent over-activation of synaptic glutamate receptors, producing spontaneous nociceptive behaviors and sensory hypersensitivity. Our results suggest that glutamate uptake through spinal glutamate transporters is critical for maintaining normal sensory transmission under physiologic conditions.

Original language	English (US)
Pages (from-to)	60-70
Number of pages	11
Journal	Pain
Volume	115
Issue number	1-2
DOIs	https://doi.org/10.1016/j.pain.2005.02.006
State	Published - May 2005

Keywords

Excitatory behavioral response
Glutamate release
Glutamate transporter
Intrathecal injection
Microdialysis
Microelectrode
Pain

ASJC Scopus subject areas

Neurology
Clinical Neurology
Anesthesiology and Pain Medicine

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10.1016/j.pain.2005.02.006

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@article{733fd722981f4560bbe773f8c77a8a0f,

title = "Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord",

abstract = "Glutamate is a major excitatory neurotransmitter in primary afferent terminals and is critical for normal spinal excitatory synaptic transmission. However, little is known about the regulation of synaptically released glutamate in the spinal cord under physiologic conditions. The sodium-dependent, high-affinity glutamate transporters are the primary mechanism for the clearance of synaptically released glutamate. In the present study, we found that intrathecal injection of glutamate transporter blockers dl-threo-β- benzyloxyaspartate (TBOA) and dihydrokainate 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. Intrathecal TBOA also led to remarkable hypersensitivity in response to thermal and mechanical stimuli. These 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. In vivo microdialysis analysis showed short-term elevation of extracellular glutamate concentration in the spinal cord after intrathecal injection of TBOA. Furthermore, topical application of TBOA on the dorsal surface of the spinal cord resulted in a significant elevation of extracellular glutamate concentration demonstrated by in vivo glutamate voltametry. The present study indicates that defective spinal glutamate uptake caused by inhibition of glutamate transporters leads to excessive glutamate accumulation in the spinal cord. The latter results in persistent over-activation of synaptic glutamate receptors, producing spontaneous nociceptive behaviors and sensory hypersensitivity. Our results suggest that glutamate uptake through spinal glutamate transporters is critical for maintaining normal sensory transmission under physiologic conditions.",

keywords = "Excitatory behavioral response, Glutamate release, Glutamate transporter, Intrathecal injection, Microdialysis, Microelectrode, Pain",

author = "Liaw, {Wen Jinn} and Stephens, {Robert L.} and Binns, {Brian C.} and Yachun Chu and Sepkuty, {Jehuda P.} and Johns, {Roger A.} and Rothstein, {Jeffery D.} and Tao, {Yuan Xiang}",

note = "Funding Information: This work was supported by the Johns Hopkins University Blaustein Pain Research Fund and NIH grants RO1 NS44219 and GM49111. The authors would like to thank Tzipora Sofare, MA, for her editorial assistance.",

year = "2005",

month = may,

doi = "10.1016/j.pain.2005.02.006",

language = "English (US)",

volume = "115",

pages = "60--70",

journal = "Pain",

issn = "0304-3959",

publisher = "Elsevier",

number = "1-2",

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TY - JOUR

T1 - Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord

AU - Liaw, Wen Jinn

AU - Stephens, Robert L.

AU - Binns, Brian C.

AU - Chu, Yachun

AU - Sepkuty, Jehuda P.

AU - Johns, Roger A.

AU - Rothstein, Jeffery D.

AU - Tao, Yuan Xiang

N1 - Funding Information: This work was supported by the Johns Hopkins University Blaustein Pain Research Fund and NIH grants RO1 NS44219 and GM49111. The authors would like to thank Tzipora Sofare, MA, for her editorial assistance.

PY - 2005/5

Y1 - 2005/5

N2 - Glutamate is a major excitatory neurotransmitter in primary afferent terminals and is critical for normal spinal excitatory synaptic transmission. However, little is known about the regulation of synaptically released glutamate in the spinal cord under physiologic conditions. The sodium-dependent, high-affinity glutamate transporters are the primary mechanism for the clearance of synaptically released glutamate. In the present study, we found that intrathecal injection of glutamate transporter blockers dl-threo-β- benzyloxyaspartate (TBOA) and dihydrokainate 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. Intrathecal TBOA also led to remarkable hypersensitivity in response to thermal and mechanical stimuli. These 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. In vivo microdialysis analysis showed short-term elevation of extracellular glutamate concentration in the spinal cord after intrathecal injection of TBOA. Furthermore, topical application of TBOA on the dorsal surface of the spinal cord resulted in a significant elevation of extracellular glutamate concentration demonstrated by in vivo glutamate voltametry. The present study indicates that defective spinal glutamate uptake caused by inhibition of glutamate transporters leads to excessive glutamate accumulation in the spinal cord. The latter results in persistent over-activation of synaptic glutamate receptors, producing spontaneous nociceptive behaviors and sensory hypersensitivity. Our results suggest that glutamate uptake through spinal glutamate transporters is critical for maintaining normal sensory transmission under physiologic conditions.

AB - Glutamate is a major excitatory neurotransmitter in primary afferent terminals and is critical for normal spinal excitatory synaptic transmission. However, little is known about the regulation of synaptically released glutamate in the spinal cord under physiologic conditions. The sodium-dependent, high-affinity glutamate transporters are the primary mechanism for the clearance of synaptically released glutamate. In the present study, we found that intrathecal injection of glutamate transporter blockers dl-threo-β- benzyloxyaspartate (TBOA) and dihydrokainate 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. Intrathecal TBOA also led to remarkable hypersensitivity in response to thermal and mechanical stimuli. These 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. In vivo microdialysis analysis showed short-term elevation of extracellular glutamate concentration in the spinal cord after intrathecal injection of TBOA. Furthermore, topical application of TBOA on the dorsal surface of the spinal cord resulted in a significant elevation of extracellular glutamate concentration demonstrated by in vivo glutamate voltametry. The present study indicates that defective spinal glutamate uptake caused by inhibition of glutamate transporters leads to excessive glutamate accumulation in the spinal cord. The latter results in persistent over-activation of synaptic glutamate receptors, producing spontaneous nociceptive behaviors and sensory hypersensitivity. Our results suggest that glutamate uptake through spinal glutamate transporters is critical for maintaining normal sensory transmission under physiologic conditions.

KW - Excitatory behavioral response

KW - Glutamate release

KW - Glutamate transporter

KW - Intrathecal injection

KW - Microdialysis

KW - Microelectrode

KW - Pain

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U2 - 10.1016/j.pain.2005.02.006

DO - 10.1016/j.pain.2005.02.006

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AN - SCOPUS:17044428937

SN - 0304-3959

VL - 115

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EP - 70

JO - Pain

JF - Pain

IS - 1-2

ER -

Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord

Abstract

Keywords

ASJC Scopus subject areas

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