TY - JOUR
T1 - Effect of inhibition of spinal cord glutamate transporters on inflammatory pain induced by formalin and complete freund's adjuvant
AU - Yaster, Myron
AU - Guan, Xiaowei
AU - Petralia, Ronald S.
AU - Rothstein, Jeffery D.
AU - Lu, Wei
AU - Tao, Yuan Xiang
N1 - Funding Information:
Received from the Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Submitted for publication July 8, 2010. Accepted for publication October 12, 2010. Supported by the National Institutes of Health (Bethesda, Maryland) Grant no. R01NS058886 , the National Natural Science Foundation of China (Beijing) Grant no. 30828015 , the Blaustein Pain Research Fund (Baltimore, Maryland), the Mr. David Koch and Patrick C. Walsh Prostate Cancer Research Fund (Baltimore, Maryland), and the Intramural Research Program of the National Institute of Deafness and Other Communication Disorders (Bethesda, Maryland). This is a work prepared by U.S. government-employed personnel. No claim is made to original works by U.S. government employees. The work is the opinion of the authors alone and not of the U.S. government. Drs. Yaster and Guan contributed equally to this work.
PY - 2011/2
Y1 - 2011/2
N2 - Background: Spinal cord glutamate transporters clear synaptically released glutamate and maintain normal sensory transmission. However, their ultrastructural localization is unknown. Moreover, whether and how they participate in inflammatory pain has not been carefully studied. Methods: Immunogold labeling with electron microscopy was carried out to characterize synaptic and nonsynaptic localization of glutamate transporters in the superficial dorsal horn. Their expression and uptake activity after formalin- and complete Freund's adjuvant (CFA)-induced inflammation were evaluated by Western blot analysis and glutamate uptake assay. Effects of intrathecal glutamate transporter activator (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline and inhibitors (DL-threo-β-benzyloxyaspartate [TBOA], dihydrokainate, and DL-threo-β-hydroxyaspartate), or TBOA plus group III metabotropic glutamate receptor antagonist (RS)-α-methylserine-O-phosphate, on formalin- and CFA-induced inflammatory pain were examined. Results: In the superficial dorsal horn, excitatory amino acid carrier 1 is localized in presynaptic membrane, postsynaptic membrane, and axonal and dendritic membranes at nonsynaptic sites, whereas glutamate transporter-1 and glutamate/aspartate transporter are prominent in glial membranes. Although expression of these three spinal glutamate transporters was not altered 1 h after formalin injection or 6 h after CFA injection, glutamate uptake activity was decreased at these time points. Intrathecal (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline had no effect on formalin-induced pain behaviors. In contrast, intrathecal TBOA, dihydrokainate, and DL-threo-β-hydroxyaspartate reduced formalin-evoked pain behaviors in the second phase. Intrathecal TBOA also attenuated CFA-induced thermal hyperalgesia at 6 h after CFA injection. The antinociceptive effects of TBOA were blocked by coadministration of (RS)-α-methylserine-O-phosphate. Conclusion: Our findings suggest that spinal glutamate transporter inhibition relieves inflammatory pain through activation of inhibitory presynaptic group III metabotropic glutamate receptors.
AB - Background: Spinal cord glutamate transporters clear synaptically released glutamate and maintain normal sensory transmission. However, their ultrastructural localization is unknown. Moreover, whether and how they participate in inflammatory pain has not been carefully studied. Methods: Immunogold labeling with electron microscopy was carried out to characterize synaptic and nonsynaptic localization of glutamate transporters in the superficial dorsal horn. Their expression and uptake activity after formalin- and complete Freund's adjuvant (CFA)-induced inflammation were evaluated by Western blot analysis and glutamate uptake assay. Effects of intrathecal glutamate transporter activator (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline and inhibitors (DL-threo-β-benzyloxyaspartate [TBOA], dihydrokainate, and DL-threo-β-hydroxyaspartate), or TBOA plus group III metabotropic glutamate receptor antagonist (RS)-α-methylserine-O-phosphate, on formalin- and CFA-induced inflammatory pain were examined. Results: In the superficial dorsal horn, excitatory amino acid carrier 1 is localized in presynaptic membrane, postsynaptic membrane, and axonal and dendritic membranes at nonsynaptic sites, whereas glutamate transporter-1 and glutamate/aspartate transporter are prominent in glial membranes. Although expression of these three spinal glutamate transporters was not altered 1 h after formalin injection or 6 h after CFA injection, glutamate uptake activity was decreased at these time points. Intrathecal (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline had no effect on formalin-induced pain behaviors. In contrast, intrathecal TBOA, dihydrokainate, and DL-threo-β-hydroxyaspartate reduced formalin-evoked pain behaviors in the second phase. Intrathecal TBOA also attenuated CFA-induced thermal hyperalgesia at 6 h after CFA injection. The antinociceptive effects of TBOA were blocked by coadministration of (RS)-α-methylserine-O-phosphate. Conclusion: Our findings suggest that spinal glutamate transporter inhibition relieves inflammatory pain through activation of inhibitory presynaptic group III metabotropic glutamate receptors.
UR - http://www.scopus.com/inward/record.url?scp=79251648330&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79251648330&partnerID=8YFLogxK
U2 - 10.1097/ALN.0b013e318205df50
DO - 10.1097/ALN.0b013e318205df50
M3 - Article
C2 - 21245732
AN - SCOPUS:79251648330
SN - 0003-3022
VL - 114
SP - 412
EP - 423
JO - Anesthesiology
JF - Anesthesiology
IS - 2
ER -