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.
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 (i.t.) DHEAS was found to significantly potentiate i.t. NMDA-induced spontaneous pain behaviors. Subsequent immunohistochemical analysis demonstrated that i.t. 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.
authors.affiliation: Department of Anesthesiology and Pain Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Seo-Yeon
authors.initials: SY
authors.lastname: Yoon
authors.forename: Dae-Hyun
authors.initials: DH
authors.lastname: Roh
authors.forename: Hyoung-Sig
authors.initials: HS
authors.lastname: Seo
authors.forename: Suk-Yun
authors.initials: SY
authors.lastname: Kang
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Moon
authors.forename: Sunok
authors.initials: S
authors.lastname: Song
authors.forename: Alvin J
authors.initials: AJ
authors.lastname: Beitz
authors.forename: Jang-Hern
authors.initials: JH
authors.lastname: Lee
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology*; D007150:Immunohistochemistry; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016202:N-Methylaspartate / Q000494:pharmacology*; D010146:Pain / Q000139:chemically induced / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects*; D011493:Protein Kinase C / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D017480:Receptors, sigma / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases; D019314:Dehydroepiandrosterone Sulfate; D016202:N-Methylaspartate; D011493:Protein Kinase C; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C409466:NR1 NMDA receptor