Abstract | BACKGROUND AND PURPOSE: 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.
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Authors | H-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 |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 154
Issue 5
Pg. 1125-34
(Jul 2008)
ISSN: 0007-1188 [Print] England |
PMID | 18493253
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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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
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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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