An increase in spinal dehydroepiandrosterone sulfate (DHEAS) enhances NMDA-induced pain via phosphorylation of the NR1 subunit in mice: Involvement of the sigma-1 receptor

Title
An increase in spinal dehydroepiandrosterone sulfate (DHEAS) enhances NMDA-induced pain via phosphorylation of the NR1 subunit in mice: Involvement of the sigma-1 receptor
Author(s)
송선옥윤서연[윤서연]노대현[노대현]서형식[서형식]강석윤[강석윤]문지영[문지영]Alvin J Beitz[Alvin J Beitz]이장헌[이장헌]
Keywords
DEHYDRO-EPIANDROSTERONE SULFATE; SPINOTHALAMIC TRACT NEURONS; EXCITATORY AMINO-ACIDS; DORSAL-HORN NEURONS; METHYL-D-ASPARTATE; INTRADERMAL INJECTION; SYNAPTIC-TRANSMISSION; INTRATHECAL INJECTION; SUBSTANTIA-GELATINOSA; MECHANICAL ALLODYNIA
Issue Date
201006
Publisher
PERGAMON-ELSEVIER SCIENCE LTD
Citation
NEUROPHARMACOLOGY, v.59, no.6, pp.460 - 467
Abstract
Our laboratory has recently demonstrated that an increase in the spinal neurosteroid, dehydroepiandrosterone sulfate (DHEAS) facilitates nociception via the activation of sigma-1 receptors and/or the allosteric inhibition GABA(A) receptors. Several lines of evidence have suggested that DHEAS positively modulates N-methyl-D-aspartate (NMDA) receptor activity within the central nervous system. Moreover, we have demonstrated that the activation of sigma-1 receptors increases NMDA receptor activity. Since NMDA receptors play a key role in the enhancement of pain perception, the present study was designed to determine whether spinally administered DHEAS modulates NMDA receptor-mediated nociceptive activity and whether this effect is mediated by sigma-1 or GABA(A) receptors. Intrathecal (it.) DHEAS was found to significantly potentiate it. NMDA-induced spontaneous pain behaviors. Subsequent immunohistochemical analysis demonstrated that it. DHEAS also increased protein kinase C (PKC)- and protein kinase A (PKA)-dependent phosphorylation of the NMDA receptor subunit NR1 (pNR1), which was used as a marker of NMDA receptor sensitization. The sigma-1 receptor antagonist, BD-1047, but not the GABA(A) receptor agonist, muscimol, dose-dependently suppressed DHEAS's facilitatory effect on NMDA-induced nociception and pNR1 expression. In addition, pretreatment with either a PKC or PKA blocker significantly reduced the facilitatory effect of DHEAS on NMDA-induced nociception. Conversely the GABA(A) receptor antagonist, bicuculline did not affect NMDA-induced pain behavior or pNR1 expression. The results of this study suggest that the DHEAS-induced enhancement of NMDA-mediated nociception is dependent on an increase in PKC- and PKA-dependent pNR1. Moreover, this effect of DHEAS on NMDA receptor activity is mediated by the activation of spinal sigma-1 receptors and not through the inhibition of GABA(A) receptors. (C) 2010 Elsevier Ltd. All rights reserved.
URI
http://hdl.handle.net/YU.REPOSITORY/22340http://dx.doi.org/10.1016/j.neuropharm.2010.06.007
ISSN
0028-3908
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의과대학 > 마취통증의학교실 > Articles
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