Sigma-1 receptor-induced increase in murine spinal NR1 phosphorylation is mediated by the PKCα and e{open}, but not the PKCζ, isoforms

Dae Hyun Roh, Seo Yeon Yoon, Hyoung Sig Seo, Suk Yun Kang, Ji Young Moon, Sunok Song, Alvin J. Beitz, Jang Hern Lee

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Our previous studies have demonstrated that intrathecal (i.t.) administration of a sigma-1 receptor agonist facilitated peripheral nociception via calcium-dependent second messenger cascades including protein kinase C (PKC). We also showed that activation of spinal sigma-1 receptors increased the phosphorylation of the NMDA receptor NR1 subunit (pNR1) in the spinal cord dorsal horn, which resulted in the potentiation of NMDA receptor function. The present study was designed to examine the effect of different PKC isoform inhibitors on sigma-1 receptor-mediated pain facilitation and increased spinal pNR1 expression in mice. The intrathecal injection of the sigma-1 receptor agonist, PRE-084 (PRE, 3. nmol/5μl) increased the frequency of paw withdrawal responses to mechanical stimuli (0.6. g) and the number of spinal pNR1-immunoreactive (ir) cells. Intrathecal pretreatment with inhibitors (Go6976, PKCe{open}V1-2 or PKC ζpseudosubstrate) of the PKCα, e{open} or ζ isoforms significantly reduced the PRE-induced pain facilitatory effect. On the other hand, the PRE-induced increase in the number of spinal pNR1-ir neurons was only blocked by inhibitors of the PKCα and PKCe{open} isoforms, but not the PKCζ isoform. These findings demonstrate that the sigma-1 receptor-induced increase in spinal pNR1 expression is mediated by the PKCα and PKCe{open} isoforms, which in turn contribute to the pain facilitation phenomenon. Conversely, the sigma-1 receptor activation of the PKCζ isoform appears to be involved in a pain signaling pathway that is independent of spinal pNR1 modulation.

Original languageEnglish (US)
Pages (from-to)95-99
Number of pages5
JournalNeuroscience Letters
Volume477
Issue number2
DOIs
StatePublished - Jun 1 2010

Keywords

  • NMDA receptor
  • Pain facilitation
  • Phosphorylation
  • Protein kinase C
  • Sigma-1 receptor

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