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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.

AbstractBACKGROUND 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.
AuthorsH-W Kim, D-H Roh, S-Y Yoon, H-S Seo, Y-B Kwon, H-J Han, K-W Kim, A J Beitz, J-H Lee
JournalBritish journal of pharmacology (Br J Pharmacol) Vol. 154 Issue 5 Pg. 1125-34 (Jul 2008) ISSN: 0007-1188 [Print] England
PMID18493253 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cyclopentanes
  • Ethylenediamines
  • Morpholines
  • NMDA receptor A1
  • NR1 NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, sigma
  • sigma-1 receptor
  • 2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate
  • N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin
  • carbetapentane
  • Serine
  • N-Methylaspartate
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
Topics
  • Animals
  • Behavior, Animal
  • Blotting, Western
  • Cyclic AMP-Dependent Protein Kinases (metabolism)
  • Cyclopentanes (administration & dosage)
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Ethylenediamines (administration & dosage)
  • Immunohistochemistry
  • Injections, Spinal
  • Male
  • Mice
  • Mice, Inbred ICR
  • Morpholines (administration & dosage)
  • N-Methylaspartate (administration & dosage)
  • Pain (chemically induced, enzymology)
  • Pain Measurement
  • Phosphorylation
  • Posterior Horn Cells (enzymology)
  • Protein Kinase C (metabolism)
  • Receptors, N-Methyl-D-Aspartate (metabolism)
  • Receptors, sigma (drug effects, metabolism)
  • Serine
  • Signal Processing, Computer-Assisted
  • Signal Transduction
  • Spinal Cord (enzymology)
  • Time Factors

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