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Activation of the spinal sigma-1 receptor enhances NMDA-induced pain via PKC- and PKA-dependent phosphorylation of the NR1 subunit in mice

Cited 80 time in Web of Science Cited 83 time in Scopus
Authors
Kim, H-W; Roh, D-H; Yoon, Seo Yeon; Seo, H-S; Kwon, Y-B; Han, H-J; Kim, K-W; Beitz, AJ; Lee, J-H
Issue Date
2008-05-19
Publisher
Wiley-Blackwell
The British Pharmacological Society
Citation
Br J Pharmacol 154: 1125-1134
Keywords
sigma-1 receptorNMDA receptorNR1 subunitphosphorylationpainmice
Abstract
Background and purpose: Previously we demonstrated that the spinal sigma-1 receptor (Sig-1 R) plays an important role in
pain transmission, although the exact mechanism is still unclear. It has been suggested that Sig-1 R agonists increase
glutamate-induced calcium influx through N-methyl-D-aspartate (NMDA) receptors. Despite data suggesting a link between
Sig-1 Rs and NMDA receptors, there are no studies addressing whether Sig-1 R activation directly affects NMDA receptor
sensitivity.
Experimental approach: We studied the effect of intrathecal (i.t.) administration of Sig-1 R agonists on protein kinase C (PKC)
and protein kinase A (PKA) dependent phosphorylation of the NMDA receptor subunit NR1 (pNR1) as a marker of NMDA
receptor sensitization. In addition, we examined whether this Sig-1 R mediated phosphorylation of NR1 plays an important
role in sensory function using a model of NMDA-induced pain.
Key results: Both Western blot assays and image analysis of pNR1 immunohistochemical staining in the spinal cord indicated
that i.t. injection of the Sig-1 R agonists, PRE-084 or carbetapentane dose dependently enhanced pNR1 expression in the
murine dorsal horn. This increased pNR1 expression was significantly reduced by pretreatment with the specific Sig-1 R
antagonist, BD-1047. In another set of experiments Sig-1 R agonists further potentiated NMDA-induced pain behaviour and
pNR1 immunoreactivity and this was also reversed with BD-1047.
Conclusions and implications: The results of this study suggest that the activation of spinal Sig-1 R enhances NMDA-induced
pain via PKC- and PKA-dependent phosphorylation of the NMDA receptor NR 1 subunit.
ISSN
0007-1188
Language
English
URI
http://hdl.handle.net/10371/8274
DOI
https://doi.org/10.1038/bjp.2008.159
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College of Veterinary Medicine (수의과대학)Dept. of Veterinary Medicine (수의학과)Journal Papers (저널논문_수의학과)
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